The animal was shot shortly after 10:15 a.m. in the Mount Vernon neighborhood, and police believe it escaped from a slaughterhouse in west Baltimore, Sgt. Sarah Connolly said.
Connolly said police received calls from business owners concerned about the animal running loose. The neighborhood is home to numerous bars, restaurants and shops.
The animal was "increasingly aggressive," and officers made several attempts to trap it before killing it, police said on the department's Facebook page.
Sam Wirtz, who lives three blocks away, said he was walking to visit a friend when he saw the animal running down the street.
"I was trying to get other people to get the hell out of the way," he said.
Wirtz said he heard four shots but didn't see the animal fall.
Police did not immediately disclose the animal's gender but referred to the animal on the Facebook page as a bull. Wirtz said that based on his experience growing up around livestock in Texas, he'd call it a bull.
"This is normal for me, just not in Baltimore city," he said.
After the shooting, police moved their cars to block from view the dark-colored animal, which was lying on its side next to a black pickup with limbs straight out.
The carcass was hauled away by representatives of a company that recycles restaurant grease and animal byproducts.