[3] Nzongola-Ntalaja's involvement in activism began during his teenage years when he participated in protests that demanded Congolese independence from Belgium.

He quickly became involved in American activism, participating in civil rights movement in the United States, pushing for the college to end discrimination against Black employees, and advocating for a more comprehensive curriculum.

[7] Nzongola-Ntalaja has extensive research on African politics,[12][13][14][5] development, and conflict issues,[15] and has authored several books and numerous articles on these topics.

[24] Nzongola-Ntalaja's open opposition to the dictator Mobutu Sese Seko and his regime in Zaire made him a target of intimidation and even death threats.

[5][25] Nzongola-Ntalaja have been a member of the African National Congress (ANC) and the Congolese People's Party for Reconstruction and Democracy (PPRD) since 1991.

In 1992, he participated as a representative in the Sovereign National Conference of Congo/Zaire,[25] followed by serving as a Diplomatic Advisor to the Transitional Government led by Prime Minister Étienne Tshisekedi.

[27] Nzongola-Ntalaja was the Permanent Representative of the Democratic Republic of the Congo to the United Nations, having presented his credentials to UN Secretary-General António Guterres on 13 January 2022.

[34] On 26 October 2022, Nzongola-Ntalaja accused Rwanda of occupying the DRC between 1998 and 2003 and committing atrocities, including plundering the Congolese economy and stealing chimpanzees and other animals.