Orphaned at fourteen, when his parents were murdered, Ketchel became a hobo and often fought with other hobos for food. He began boxing professionally in 1903. During an eight-month stretch in 1905, he knocked out fourteen opponents in a row, winning his nickname, the "Michigan Assassin."
Ketchel won the vacant world middleweight title on February 22, 1908, when he knocked out Mike "Twin" Sullivan in the 1st round at Colma, CA. After three defenses, he lost the championship to Billy Papke on September 7, 1908, in Los Angeles. When the fighters met in the center of the ring for the traditional handshake before the bout, Papke knocked Ketchel down. Fighting in a daze, Ketchel was knocked down three more times in the first round, but he managed to last into the 12th round, when he was knocked out.
In a rematch on November 28 in San Francisco, Ketchel won the title back with an 11th-round knockout. He defended the championship four times and then met Jack Johnson for the heavyweight title on October 16, 1909. Outweighed by about fifty pounds, Ketchel more than held his own for 11 rounds. He knocked Johnson down with the first punch of the 12th round, but Johnson got up and knocked Ketchel out with a tremendous right hand.
Ketchel was training on a farm in Conway, MO, for a 1910 fight when he got involved with a female cook. He was shot to death by a jealous farmhand, Walter Dipley.
Ketchel won 53 bouts, 50 of them by knockout; lost 4, 2 by knockout; and fought 4 draws and 4 no-decisions.