McKeldin attended high school at Baltimore City College in the evenings while working as a bank clerk during the day.

McKeldin challenged Democratic mayor of Baltimore Howard W. Jackson in the 1939 election, but was defeated.

He subsequently challenged the incumbent governor of Maryland, Democrat Herbert R. O'Conor, in 1942, but lost by five points.

McKeldin ran for governor again in 1946, challenging William Preston Lane Jr., but was defeated again by a wider margin than in 1942.

After his second term in Government House, McKeldin returned to his law practice in Baltimore; he was succeeded as Governor by Democrat J. Millard Tawes.

In 1963, McKeldin returned to public service after being narrowly elected to a second non-consecutive term as mayor of Baltimore.

[6] In 1966, the city council voted to condemn and demolish 700 homes in the Rosemont neighborhood to build the Interstate 170 "highway to nowhere" that McKeldin had conceived with urban planner Robert Moses in 1941.