Manchin beat former Monongalia County legislator Sheirl Fletcher, a former Republican who questioned Manchin's Democratic allegiance.
Manchin will face Republican John Raese, who was unopposed on Tuesday. The two first faced off in a 2010 special election two months after the death of U.S. Sen. Robert C. Byrd.
Raese's campaign already has launched a radio ad challenging Manchin's support for Obama's health care plan.
Manchin came under recent scrutiny for saying he's not sure whether he'll vote for President Barack Obama or presumptive Republican nominee Mitt Romney in November.