Niekro was the Opening Day starter for the Astros to start the 1981 season. It was only the second time in his career as opening-day starting pitcher since doing so as a Cub thirteen years prior. Facing the Dodgers at Dodger Stadium, he went seven innings while allowing two runs on eight hits in the 2-0 loss. He reached the 1,000 strikeout plateau on April 19, doing so on a strikeout bunt by Vance Law. He went 9-9 in 24 games pitched with a 2.82 ERA in 166 innings while striking out 77 batters and walking 47. He appeared in Game 2 of the 1981 National League Division Series against the Los Angeles Dodgers, pitching eight scoreless innings, although Joe Sambito ended up being the winning pitcher for the Astros as they won in the 11th inning, though the Dodgers would win the series in five games. He displayed a bit more effectiveness the following year. He went 17-12 in 35 games with a 2.47 ERA and 270 innings pitched while having a career-high 16 complete games and five shutouts. He struck out a career-high 130 batters while walking 64 and leading all of Major League Baseball with 19 wild pitches.