Some Enchanted Evening when they failed to take the chance to have Miss Botz murder Marge and become the new Mrs Simpson and step mother to Bart, Lisa and Maggie. Imagine the funny hijinx that would've ensued!
I mainly blame Good Night for the downfall; converting the main cast from bipedal rabbits into misshapen yellow goblins was a pretty irrevocable error and majorly damaged the show's resonance going forward.
The Simspsons went downhill at the end of A Totally Fun Thing Bart Will Never Do again, as you can see here. Homer also went down Springfield Gorge but that wasn't the whole family so I'm not counting it.