It's really hard to pick, but it'd have to come from seasons 1-4. Season one is more endearing & realistic, but seasons 2-4 are a lot funnier with more of the stuff I remember about the show.
While the show is pretty consistently good, I felt like its 'feel' changed when they moved into high school. When Jamie was born at the end of season 4, that's the last we see of the Krelboynes, which eliminated the friend group for Malcom, which I never liked. The plots also get a lot more ridiculous and the show becomes a lot less grounded after season 4, with stuff like Lois traveling to globe to find Reese or Malcom dating a whole family. And while still really good, it lost a bit of the magic of the earlier seasons.
The worst thing they did was with how they regressed Francis's character in the later seasons, and then killed off his entire arc with Otto and Gretchen with a crappy joke about bankrupting them with a fake ATM. Like I know Otto's actor was having health issues, but they could have done it more justice than that.