Lu was a Peace Corps volunteer in Sierra Leone, West Africa in 1988-1990 helping restore hand-dug water wells, and teach health education and latrine construction.

He served as special assistant to the ambassador for the Newly Independent States from 2000 to 2001, and then as deputy director in the Office of Central Asian and South Caucasus Affairs from 2001 to 2003.

In July 2010, Lu was appointed Deputy Chief of Mission at the United States Embassy in New Delhi, India.

[12] On April 23, 2021, President Joe Biden nominated Lu to be the Assistant Secretary of State for South and Central Asian Affairs.

[16][17] Although the State Department denied it, Khan reiterated the allegations against Lu during a televised news conference.

[24] Furthermore, Pakistan's Inter-Services Public Relations (ISPR) director general (DG) major-general Babar Iftikhar commented on the issuance of the demarche during a press conference on April 14, stating that "In this case, it was given for undiplomatic language and is equal to interference.

"[25][26] Shireen Mazari, a Pakistani politician who served as the federal minister for human rights under the PTI government, quoted Donald Lu as saying: "If Prime Minister Imran Khan remains in office, then PM Imran Khan will be isolated from the United States and we will take the issue head on; but if the vote of no-confidence succeeds, all will be forgiven".

[27] On 23 May 2022, Imran Khan suggested in an interview with CNN that Lu be fired "for bad manners and sheer arrogance.

"[28] On 9 August 2023, The Intercept, an online American nonprofit news organization, published a copy of the previously undisclosed cypher—a secret Pakistani cable document—from March 7, 2022, clearly demonstrating the pressure from the U.S. State Department to remove then Prime Minister Imran Khan.

In addition to English, Lu speaks Chinese, West African Krio, Urdu, Hindi, Russian, Georgian, Azerbaijani and Albanian.