Amenhotep rose through the ranks of government service, becoming scribe of the recruits, a military office, under Amenhotep III. While in the Nile River delta, Amenhotep was charged with positioning troops at checkpoints on the branches of the Nile to regulate entry into Egypt by sea; he also checked on the infiltration of Bedouin tribesmen by land. On one of his statues, he is called a general of the army.

Some time later, when he was placed in charge of all royal works, he probably supervised the construction of Amenhotep III's mortuary temple at Thebes near modern Luxor, the building of the temple of Soleb in Nubia (modern Sudan), and the transport of building material and erection of other works. Two statues from Thebes indicate that he was also an intercessor in Amon's temple and that he supervised the celebration of one of Amenhotep III's Heb-Sed festivals (a renewal rite celebrated by the pharaoh after the first 30 years of his reign and periodically thereafter). The king honoured him by embellishing Athribis, his native city. Amenhotep III even ordered the building of a small funerary temple for him next to his own temple, a unique honour for a nonroyal person in Egypt.

Amenhotep was greatly revered by posterity, as indicated by the reinscription of the donation decree for his mortuary establishment in the 21st dynasty (Egypt, ancient) (1075–c. 950 BCE) and his divine association with Asclepius, the Greek god of healing, during the Ptolemaic period.