Wordorigins.org

A southpaw is a left-hander or the left hand. Today, the word is primarily used in baseball, but appears in other contexts as well. But despite its use in baseball, the term almost certainly did not originate with that sport. Instead, it is more likely from the world of boxing.

The earliest known use of southpaw is in a political cartoon from 1848 titled Democratic B-Hoy (boy). The cartoon depicts Democratic presidential candidate Lewis Cass in a brawl with Zachary Taylor and a number of other Whigs. In the cartoon Cass is winning the fight, although in actuality he lost the election to Taylor. One of the Whigs, who has been knocked to the ground, says:

Curse the Old Hoss, what a south paw he has given me!