Before his inauguration, rumors in the city of an assassination plot against Abraham Lincoln, who was on his way to Washington, D.C., forced the president-elect to sneak through Baltimore in the middle of the night. Anti-Union sentiments there only increased once the hostilities commenced at Fort Sumter on April 12. A week later, one of the first regiments to respond to Lincoln's call for troops arrived in Baltimore by train, en route to the capital. Because the rail line did not pass through the city, horse drawn cars had to take the Massachusetts infantrymen from one end of Baltimore to the other. An angry crowd of secessionists tried to keep the regiment from reaching Washington, blocking several of the transports, breaking windows, and, finally, forcing the soldiers to get out and march through the streets. The throng followed in close pursuit. What had now become a mob surrounded and jeered the regiment, then started throwing bricks and stones.

Panicking, several soldiers fired randomly into the crowd, and mayhem ensued as the regiment scrambled to the railroad station. The police managed to hold the crowd back at the terminal, allowing the infantrymen to board their train and escape, leaving behind much of their equipment as well as their marching band. Four soldiers and twelve civilians were killed, and scores were injured. Maryland officials demanded that no more Federal troops be sent through the state, while Baltimore's mayor and police chief authorized the destruction of key rail bridges to prevent Union troops from entering the city. Secessionist groups, meanwhile, tore down telegraph wires to Washington, temporarily cutting the capital off from the rest of the nation. The North was outraged; New York Tribune editor Horace Greeley even called for Baltimore to be burned to the ground.

On May 13, Federal troops, including members of the Massachusetts regiment attacked in the previous month's riot, occupied the city and martial law was declared, squelching most subsequent pro-Confederate activities. The police chief, several commissioners, and a number of citizens were arrested for their alleged participation in the riot, and suspected secessionists, including Francis Scott Key's grandson and a number of state legislators, were held without charges. Federal forces continued to maintain an occupying presence in Baltimore for the remainder of the war.