First, no matter how silly The Simpsons may ever be, Family Guy is always sillier. I like fiction to have a certain degree of seriousness or else I won't have the emotional investment needed to value it highly. For example, while an episode of The Simpsons may be about the family sleeping through church, waking up to find that it is Judgement Day and then heading down into Hell, an episode of Family Guy may have a character say in the rain on the street "Could this day get any worse?" only to have somebody run over and stab them. Now, I won't deny, I laughed at that, I thought it was a very funny joke, but the thing is, in the next scene they were fine with no mention of being stabbed. It was just utterly meaningless; only there to make the audience laugh. Obviously, with The Simpsons example the family aren't trapped in Hell from then on, and that's never mentioned again either, but I see quite a difference here. The Hell ending does more than just making the audience laugh: it's quite unsettling too and makes the ending quite disturbing. Also, the episode had been about the family dreaming while in church, all of them dreaming about themselves living the lives of various characters from The Bible. The episode based on Bible stories ends with Judgement Day much as The Bible itself does, which is probably intentional. Furthermore, it's not too hard to reconcile that ending with other episodes; each of them had been having dreams throughout the episode, and that ending could easily be another dream. But the stabbing example cannot even be reconciled with the episode it’s a part of.
Another good example is to look at how each series has handled crossovers in the past. The Simpsons did an episode which was a cross over with The Prisoner and Family Guy has done an episode which crossed over with House. The Simpsons/Prisoner episode didn't do anything drastic to the character of Number 6 and he was generally portrayed much as he was in his original series, if you wanted to, you could fit that somewhere into the story of The Prisoner. Meanwhile, when Gregory House appears in Family Guy he is pretty much a parody of himself: somebody says 'if you're a doctor, you'll need this' and hands him 'The Rule Book' which makes House really angry and so he throws the book out of the window and later you find out that House was actually a criminal who dressed as a monster to terrorise people and, at the same time was an English man doing a fake American accent...
Which brings me to my next point: Family Guy does seem to use meta-fictional humour an awful lot. Somebody will say something and somebody will reply "Wow, I thought we had a clip for that!" or, say, introduce a live action singer to play them out, as if it were some kind of live variety show. I don't mind meta-humour, and sometimes I even enjoy it, but being constantly reminded that these are just characters takes you right out of the world and reduces integrity. It also makes me care much less about any of the characters: if they know they're fictional and can be stabbed one scene and completely fine the next, then why should I worry about them? If something bad happens, none of them should care, they'll have no reason to worry since they know it's always fine. A ‘Treehouse of Horror’ episode of The Simpsons often makes me a bit uncomfortable because these loveable characters are being murdered or going through horrible events, but anytime there's a threat or something similar in Family Guy, I simply don't care about them.
Now, I don't want to sound too critical, I often laugh at the jokes in Family Guy, but, to me, that's all it is, something to laugh at. The Simpsons, on the other hand is a show about a family with interesting stories, loveable characters and lots of good jokes too. I do like Family Guy, but it will never be a favourite of mine (like The Simpsons is) simply because it is so silly, and if it can't take itself at all seriously, why should I?