Born in Los Angeles, California, Wolpe was an associate professor at Western Michigan University and a Kalamazoo City Commissioner before serving in the Michigan House of Representatives from 1973 to 1976. He first ran for Congress in 1976 but lost to Garry Brown. In 1978 he was elected to the 96th Congress and was re-elected six times. In Congress, Howard Wolpe chaired the Subcommittee on Africa of the House Foreign Affairs Committee for 10 years. He also chaired the Investigations and Oversight Subcommittee of the House Science, Space and Technology Committee. His other roles in the Congress included the co-chairmanship of the bipartisan Northeast-Midwest Congressional Coalition and the Congressional Energy and Environmental Study Conference.

In 1994, he won the Democratic nomination for Governor of Michigan and selected his former rival in the Democratic primary, state senator Debbie Stabenow (now a US Senator), as his nominee for Lieutenant Governor. The Wolpe-Stabenow ticket lost the general election to incumbent Governor John Engler and Lieutenant Governor Connie Binsfeld.

He later served as President Bill Clinton's Special Envoy to the Great Lakes Region of Africa, where he led the United States delegation to the Arusha peace talks, which aimed to end civil war in the war-torn nation of Burundi.

He is currently the Director of the Africa Program and the Project on Building State Capacity at the Woodrow Wilson International Center for Scholars, part of the Smithsonian Institution, where he leads capacity-building efforts in Burundi, the Democratic Republic of Congo and Liberia. He is an endorser of the Genocide Intervention Network.

Howard Wolpe lives near Washington, D.C..