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."
Rep. Chris Van Hollen, the Montgomery County Democrat who also is a top voice on fiscal issues in his party, summed up Mikulski's status as a cheerleader for her causes.
"When Barbara Mikulski is with you," Van Hollen quipped, "the Force is with you."
Mikulski made several appearances on the Senate floor Wednesday to address her latest concern — securing federal aid for Eastern Shore residents whose homes and businesses were damaged by Hurricane Sandy. Federal officials have ultimately provided additional money for hard-hit Somerset County.
"I'm glad that on the day that this happened I was on the Senate floor speaking up for Crisfield," she said.