After the death of Champollion, Lepsius made a systematic study of the French scholar's Grammaire égyptienne, which had been published posthumously in 1836 but had yet to be widely accepted.

In 1842, Lepsius was commissioned (at the recommendation of the minister of instruction, Johann Eichhorn, and the scientists Alexander von Humboldt and Christian Charles Josias Bunsen) by King Frederich Wilhelm IV of Prussia to lead an expedition to Egypt and the Sudan to explore and record the remains of the ancient Egyptian civilization.

[7] Lepsius reached as far south as Khartoum, and then travelled up the Blue Nile to the region about Sennar,[citation needed] where he met members of the former Sudanese royal family, such as Nasra bint 'Adlan.

[8] After exploring various sites in Upper and Lower Nubia, the expedition worked back north, reaching Thebes on November 2, 1844, where they spent four months studying the western bank of the Nile (such as the Ramesseum, Medinet Habu, the Valley of the Kings, etc.)

These plans, maps, and drawings of temple and tomb walls remained the chief source of information for Western scholars well into the 20th century, and are useful even today as they are often the sole record of monuments that have since been destroyed or reburied.

In 1866 Lepsius returned to Egypt, where he discovered the Decree of Canopus at Tanis, an inscription closely related to the Rosetta Stone, which was likewise written in Egyptian (hieroglyphic and demotic) and Greek.

He was the editor of the Zeitschrift für ägyptische Sprache und Altertumskunde, a fundamental scientific journal for the new field of Egyptology, which remains in print to this day.

Lepsius published widely in the field of Egyptology, and is considered the father of this modern scientific discipline, assuming a role that Champollion might have achieved, had he not died so young.