At a news conference in Annapolis, Szeliga vowed to replicate the upset Larry Hogan pulled off 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 GOP nod are former gubernatorial aide Chrys Kefalas, Navy veteran Anthony Seda and former Pentagon official Richard Douglas.
Szeliga, pronounced shuh-LEG-uh, has represented Baltimore and Harford counties 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 would likely face an uphill race against one of the Democratic U.S. House members seeking their party's nomination. Reps. Chris Van Hollen and Donna Edwards are announced candidates, while Rep. Elijah E. Cummings has not ruled out joining the race.
No Republican has represented Maryland in the United States Senate since Mikulski won the seat vacated by the late Sen. Charles McC. Mathias Jr. in the 1986 election.
Because Szeliga is running in a presidential election year, she will not have to give up her seat in the legislature. She said she will continue to serve as minority whip as she campaigns.
One factor beyond Szeliga's control is who will head the Republican ticket out of a presidential field that includes such unconventional candidates as Donald Trump and Dr. Ben Carson.
"I will support whoever the party elects," she said. "I like 'em all."
Szeliga was joined for her announcement by more than a dozen current and past Republican elected officials. Anne Arundel County Executive Steve Schuh, a former House colleague, introduced her as "a mainstream conservative" who would bring balance to the state's Democrat-dominated congressional delegation.
Del. Robert L. Flanagan, a Howard County Republican who attended the announcement, welcomed her entry.
"It gives us real credibility," he said. "She's a charismatic, thoughtful candidate who can appeal to Marylanders."
One question looming over Szeliga's candidacy — if she can win the primary — is whether she would be able to raise enough money to compete with the Democratic nominee. Szeliga said she was not recruited to run by national Republicans but expressed hope that the national party would see Maryland as "a great place to invest in 2016."
Flanagan predicted the Democrats would spend heavily on a primary battle and start from the same place as the eventual Republican nominee.
"Coming out of the primary, both sides will have an opportunity to raise money," he said. "Once the voters start to take notice of Kathy, she'll be able to raise money."
Szeliga, who lives in Perry Hall, introduced herself as a woman who married young and worked her way up earning the minimum wage as a dishwasher, parking lot attendant, maid and waitress before earning an education degree from Towson University when she was 32. She said she worked briefly as a long-term substitute in Baltimore schools before joining her husband Mark's construction business.
From 2004 to 2010, Szeliga served as chief of staff to then-state senator and current U.S. Rep. Andy Harris.
If elected to the Senate, Szeliga said she would focus on three goals: improving the American quality of life, bolstering national security and improving schools. One issue she stressed was improving vocational education, arguing that too many young people are pushed into four-year colleges.
"You don't need a college degree to be a good carpenter, welder, plumber, auto mechanic, member of the armed forces or firefighter," she said. "Mark and I have made a great life in the construction trades — one of the many careers available that don't require four years of college."