Niekro was drafted by the Cleveland Indians in the seventh round of the 1966 amateur draft, but he did not sign with the club. On June 7, he was drafted in the third round of the draft by the Chicago Cubs. Niekro went 10–7 in 1967, throwing 169.2 innings while having a 3.34 ERA and 77 strikeouts. Niekro started the following season's Opening Day game for the Cubs at Crosley Field against the Cincinnati Reds. He went 4 1/3 innings while giving up five runs on six hits in a 9-4 loss. For the year, he went 14–10 while throwing 177.1 innings on a 4.31 ERA while having 65 strikeouts. He was traded along with Gary Ross and Frankie Librán from the Cubs to the expansion San Diego Padres for Dick Selma on April 24, 1969. His combined total for the season was 8–18, throwing 62 strikeouts in 221.1 innings while having a 3.70 ERA. Along with Al Santorini, he led the Padres in wins with eight.