At a news conference in Annapolis, Szeliga vowed Tuesday to replicate the upset pulled off by fellow Republican Larry Hogan in 2014 when he won the governor's race in heavily Democratic Maryland.
"The people are ready for new representation," she said. "They're not looking for career politicians and business as usual."
Szeliga, 54, gives the GOP its most prominent contender so far for the seat Mikulski has held for three decades. Also seeking the Republican nomination are former gubernatorial aide Chrys Kefalas, Navy veteran Anthony Seda and former Pentagon official Richard Douglas.
Szeliga has represented Baltimore and Harford counties in the House of Delegates since 2011. She was elected minority whip in 2013, making her the highest-ranking Republican woman in the General Assembly.
If she wins the nomination, Szeliga will likely face an uphill race against one of the Democratic House members seeking their party's nomination.
Reps. Donna Edwards of Prince George's County and Chris Van Hollen of Montgomery County entered the race shortly after Mikulski announced her retirement in March. Rep. Elijah E. Cummings of Baltimore has not announced a decision on the race.
Registered Democrats in Maryland outnumber Republicans by more than 2 to 1. The last Republican to represent the state in the Senate was Charles McC. Mathias, who retired in 1987.