Van Hollen led Republican challenger Kathy Szeliga 82 percent to 16 percent with 0.5 percent of precincts reporting.
Van Hollen had been expected to replace Mikulski in a Senate race that was rated Safe Democrat by The Rothenberg & Gonzales Political Report/Roll Call.
Van Hollen’s election to the Senate leaves an open seat on the powerful House Budget Committee, which will change the Democratic leadership ladder in the House, albeit at its lowest rung.
The Maryland Democrat is considered a darling of establishment party leaders.
During her campaign, Szeliga hoped to ride a GOP wave that in 2014 elected a Republican governor in a blue state. The Baltimore County Republican serves as minority whip in Maryland’s House of Delegates.
Van Hollen and Szeliga clashed during a heated debate in October when the rivals brought starkly different ideas about how to govern.
The event also witnessed a third-party candidate, Margaret Flowers, storming the stage to demand she be included in the debate. She was eventually removed.
Van Hollen defeated fellow Maryland Democratic Rep. Donna Edwards in a heated primary in April.
Mikulski’s retirement and Edwards’ departure leaves open the possibility of Maryland having an all-male congressional delegation for the first time in decades.
“What a shame it would be if Maryland [voters] did not have a woman representing them in Washington,” Szeliga said in their recent debate, a line Edwards had used against Van Hollen during the Democratic primary.