Waner broke into the major leagues with the Pirates in 1927 and quickly built his reputation as a slap hitter with an astute sense of plate discipline. In his rookie campaign, he batted .355 with 223 hits while only striking out 23 times (the highest strikeout total of his career). As the leadoff hitter of the powerful Pittsburgh offense, he led the National League (NL) with 133 runs scored. The runs scored mark set an MLB rookie record. Al López said that infielders of the era played deep at their positions, but Waner made them play closer to compensate for his speed as a runner.
Paul was known as "Big Poison" and Lloyd as "Little Poison". They got their nicknames from a Brooklyn Dodgers fan's pronunciation of "Big Person" and "Little Person", which was then picked up by a sportswriter in the stands. In 1927, the season the brothers accumulated 460 hits, the fan is said to have remarked, "Them Waners! It's always the little poison on thoid (third) and the big poison on foist (first)!"