However, at the time of Tutankhamun's death, Egypt was engaged in a fairly major confrontation with the Hittites that ended in a defeat at Amqa not far from Kadesh. Though we do not know whether Horemheb was leading the Egyptian troops in this battle, he appears to have been not much involved in Tutankhamun's funerary arrangements despite his high position may suggest that he was out of the country at this time. It may also explain Ay's ascent to the throne at that time.

The pharaoh's birth name and epithet was Horemheb meryamun, meaning "Horus is in Jubilation, Beloved of Amun". His name is also sometimes spelled Horemhab, or Haremhab. His throne name was Djeserkheperure Setepenre, meaning "Holy are the Minifestations of Re, Chosen of Re" 

It is clear that General Horemheb was an ambitious man, and so upon the death of Ay, he declared himself king of Egypt in about 1321 BC. It is really unknown to what extent he seized power, for he can be seen as Ay's heir on a relief from the tomb of the High Priest of Ptah, Ptahemhat-Ty. However, as king, a coronation statue now in Turin recounts how his local god, Horus of Hnes (Hutnesu), elevated him to the throne, which might be seen as justification of his having won some struggle for power after Ay's death. In the Turin stela, he goes on to record how he was carefully prepared for his role as king as the deputy and prince regent of Tutankhamun. Eventually, it is Horus of Hnes that presents him to Amun during the Opet Festival procession, and then who proceeds to crown him as king. Hence, though he makes no claim to be of royal blood, he becomes divinely elected to the throne by means of an oracle.  

A middle aged man by the time of his ascent to the throne, he consolidated his rise to pharaoh by marriage to a lady named Mutnodjmet, who was a songstress of Amun as well as perhaps the sister of Nefertiti (though some authorities disagree on this matter), Akhenaten's widow. Hence, he formed a link back to the female royal blood line, though perhaps somewhat tenuously. From a recently rediscovered tomb at Saqqara, he appears to have had an earlier wife, perhaps by the name of Amenia.  From the bones recovered from Horemheb's Saqqara tomb, it is believed that Mutnodjmet, who was in poor health at the time, may have died at the age of 45 while attempting to give birth to a child during the king's 13th year as ruler. No other children seem to have outlived the pharaoh.

He probably felt, and perhaps rightly so, that Egypt was in need of strong leadership after the Amarna Period, and though the transition had begun as early as the reign of Tutankhamun, he also sought to complete the return to Egypt's traditional religion. It appears that it was during the reign of Horemheb that the first attempts were made to write the Amarna Period out of Egyptian History, and he is often credited with reopening and repairing the temples of Amun, as well as restoring its priesthood. However, realizing the problems that this powerful priesthood caused for previous kings, he had military men who's loyalties he could trust appointed as priests.

Though some official presence remained at Amarna, it was probably occupied with the dismantling of buildings so that the stone could be used elsewhere. He was surely responsible for the demolition of the Aten temples at Karnak. The stone from these structures was reused in the foundations and filling of Horemheb's own building projects to Amun-Re. Specifically, these building projects at Karnak included the commencement of the mammoth Hypostyle Hall, together with the Ninth and Tenth Pylons. However, in using the building materials of Akhenaten's previous structures for fill, he inadvertently preserved them so that today's Egyptologists have been able to reconstruct from this fill many complete scenes from the Amarna period. At Luxor, he continued the work of Amenhotep III and Tutankhamun, usurping the latter's monuments both there and elsewhere. Perhaps much of the work completed during the reign of Tutankhamun was actually commissioned by Horemheb for today, many of the statues and reliefs bearing Horemheb's cartouches was actually work completed during Tutankhamun's reign.

In addition to Horemheb's efforts of religious restoration, a stela on the north face of the Tenth Pylon at Karnak, which was duplicated at Abydos, describes the king's desire to remedy various excesses committed by servants of the state. Though these documents known as the Great Edict of Horemheb, he apparently invoked harsh punishments for those found guilty of corruption. Abuses included the unlawful requisitioning of boats and slaves, the theft of cattle hides, the illegal taxation of private farmland and fraud in assessing lawful taxes and the extortion of local mayors by officials responsible for organizing the king's annual visit to the Opet Festival. Convicted officials faced the removal of their noses and then exile, while soldiers who stole animal hides, for example were subject to a hundred blows and five open wounds. In fact, there seems to have been a whole body of laws intended to stamp out widespread bribery and corruption. Many of these problems have been viewed as the result of the iconoclastic policy of Akhenaten, whose disruption of the traditional temple based economy had opened the door to all kinds of excesses by local administrators, as well as military officials. 

However, Akhenaten had been dead for about fifteen years when Horemheb came to the throne, and some Egyptologists question whether these reforms were undertaken during the reign of Horemheb, or instead represented the king's recounting of reforms he had overseen as an official of Tutankhamun. It should be noted that no king's name appears on the previously mentioned stela, though it has been attributed to Horemheb because his cartouche was recorded on the lunette (rounded upper part of the stela).

Regardless of these efforts, there was apparently several instances of tomb vandalism during the reign of Horemheb. We know that the tomb of Tuthmosis IV was robbed and then restored in Horemheb's eighth year as ruler. Graffiti recording the restoration credits Maya with the work, and he was probably also responsible for the re-closure of Tutankhamun's tomb, which also seems to have suffered the attention of robbers. 

Possibly because he was no longer primarily a military man after rising to the throne of Egypt, he sought to consolidate his hold over the army by dividing it under two separate commanders, one for the north (Lower Egypt) and the second for Egypt's southern region (Upper Egypt). Though the restoration of Egypt's traditional religion occupied much of Horemheb's reign, there were some military operations that were undertaken, some of which may have simply been to follow up on actions initiated during the reigns of his predecessors. Though most of these seem to have been strictly limited, reliefs on the north face of the Tenth Pylon and on the adjacent courtyard walls at Karnak evidence a Syrian campaign, though little else is known of these. In fact, at times we learn more about his confrontations with the Hittites from sources outside Egyptian texts, including one Hittite text that refers to a possible peace treaty that may have been effected during his reign. From other inscriptions at Karnak, we also learn of a possible trading expiation to the land of Punt. Horemheb's rock cut sanctuary at Silsila also speaks of a Nubian operation. 

We also know that the burial of two Apis bulls at Saqqara can be attributable to the reign of Horemheb. They were buried in two rooms of a single tomb. 

Though official records of Horemheb's reign credit him with as many as 59 years on the throne, these incorporate the pharaohs of the Amarna period. Later kings would also omit the Amarna period pharaohs from various king's lists, including the Ramesside records at Abydos and Karnak.  On the other hand, the highest unequivocal record for the length of his reign is thirteen years. Nevertheless, a 27th year is mentioned in a graffiti on a statue in his mortuary temple, which was probably near the end of his life. Hence, many Egyptologists believe he reigned for about thirty years. Upon his death, there being apparently no children as heirs to the throne of Egypt, he chose Paramesse, who was perhaps his northern Vizier, as his successor. The new king would become Ramesses I, who founded Egypt's 19th Dynasty. 

Horemheb's close colleague during his early years, Maya, almost certainly served Akhenaten at Amarna and was probably the same person as May, who owned a tomb at Amarna. Both Horemheb and Maya also had superbly decorated tombs built for themselves at Saqqara during the reigns of Tutankhamun and Ay. The tomb attributed to Horemheb was very large, and reliefs recovered from its ruins in the 19th century were of the highest quality. On Horemheb's accession to the throne of Egypt, he had uraei added to the brows of his figures in his tomb at Saqqara, so perhaps he had a brief thought of making it his regal tomb. However, that tomb was used for the burial of Horemheb's two known wives, and he eventually had a conventional royal tomb (KV57) dug in the Valley of the Kings on the West Bank at Thebes (modern Luxor), although its decorations were never completed. Some have used the fact that this tomb was incomplete as evidence that his reign was shorter than most Egyptologists now believe. He also usurped the mortuary temple of Ay at Medinet Habu for his own, rebuilding it on a much larger scale.

Many of Horemheb's successors in the 19th Dynasty considered him to be the founder of their line, which probably explains why a number of officials together with some royalty, such as princes Tia, the sister of Ramesses II, located their tombs near his at Saqqara.

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