He and his younger brother Lloyd, nicknamed "Little Poison," hold the career record for hits by brothers, outpacing Joe DiMaggio and his two brothers Dom and Vince, and the three Alou brothers Felipe, Matty and Jesús, among others. A possibly apocryphal story claims that he and his brother's nicknames reflect a Brooklyn Dodgers fan's pronunciation of "Big Person" and "Little Person"; but given that Lloyd was actually taller, this would seem somewhat incongruous. For most of the period from 1927 to 1940, Paul patrolled right field at Forbes Field while Lloyd covered the ground next to him in center field.

After playing the first fifteen years of his career with the Pirates, he ended his career playing for the Dodgers (1941, '43-44), Boston Braves (1941-42) and New York Yankees (1944-45). Famous for his ability to hit while hung over, when Waner gave up drinking in 1938 at management's request, he hit only .280 - the only time that he failed to hit .300 as a Pirate. As Casey Stengel said in complimenting his base-running skills, "He had to be a very graceful player, because he could slide without breaking the bottle on his hip."

Waner was also nearsighted, a fact that Pirate management only learned late in his career when he remarked that he had difficulty reading the ads posted on the outfield walls. Fitting him with glasses, however, only interfered with his hitting, as Waner now had to contend with a small spinning projectile rather than the fuzzy grapefruit-sized object he had been hitting before.

Waner died in Sarasota, Florida at age 62. In 1999, he ranked Number 62 on The Sporting News' list of the 100 Greatest Baseball Players, and was nominated as a finalist for the Major League Baseball All-Century Team.