He went to Providence Classical High School before attending Harvard University from 1888,[1] graduating in 1892 and receiving his master's degree in 1897.

[4] In 1899 Lythgoe went to Egypt to undertake archaeological work, assisting George Reisner in the Hearst Expedition at Naga ed-Der, 1899–1904.

He directed a number of Egyptian excavations for the Metropolitan Museum, employing his former Harvard student Herbert Winlock.

[3] As curator, he was also responsible for the arrangement of the Metropolitan Museum's Egyptian Collection in New York, which won praise from other Egyptologists.

On hearing of the discovery Lythgoe, who was working at the Metropolitan's nearby Deir al Bahari excavation, sent a congratulatory telegram to Carter.

Carter later wrote: In my reply [to Lythgoe] I somewhat diffidently inquired whether it would be possible — for the immediate emergency at any rate — to secure the assistance of Mr Harry Burton, their photographic expert.

He attended the opening of the burial chamber in February 1923,[11] and when Carter and his patron Lord Carnarvon sold exclusive reporting rights to The Times, a deeply unpopular move with the rest of the world's press, Lythgoe wrote to Edward Robinson, the Metropolitan's director, that 'although we are doing the lion's share of the work, the tomb is Carnarvon's and Carter's and the right to speak publicly of it ... is solely theirs'.