He was an associate professor at the University of KwaZulu-Natal, where he taught a masters course on Current Legal Issues: The Politics of Law, and where he is still a research fellow.

[4][8] Du Plessis acted as Lead Counsel on behalf of Mozambique's Forum for Monitoring the Budget (FMO) in the Tuna Fishing Boats Affair regarding former finance minister Manuel Chang's extradition to the United States.

[9] In 2022 and 2023, du Plessis, on behalf of the Campaign for Free Expression, argued in court that former President Jacob Zuma's attempts to prosecute journalist Karyn Maughan amounted to a SLAPP lawsuit.

[10] In 2023, du Plessis acted for South Africa's opposition party the Democratic Alliance (DA) to secure a declaratory order from the country's High Court that Russian President Vladimir Putin would be arrested if he arrived in South Africa for the BRICS Summit.

[11][12] In January 2024, du Plessis appeared in the Hague as a member of the legal team representing South Africa's proceedings accusing Israel of genocide at the International Court of Justice (ICJ).