She was last elected in 2010, beating Republican candidate Eric Wargotz with more than 60 percent of the vote.
Mikulski, a former social worker and member of the Baltimore City Council, began her political career in the late 1960s when she organized neighbors to block the expansion of Interstate 83 through Fells Point.
Her pending chairmanship was cheered by other members of Maryland's congressional delegation.
"Senator Barb has been shattering glass ceilings her entire career," Democratic Sen. Ben Cardin, Maryland's junior senator, said in a statement. "As our nation's fragile recovery continues to pick up steam, Chairman Mikulski will help ensure that we find a path forward that keeps the federal government invested in job-creating, growth-friendly projects and programs."