Firstly and most importantly, the ending. Bioware lied about co-op being required to get all results (which really pissed me off, as I had no interest in co-op play, and I'm one of those perfectionists who likes to complete it in every way possible) until the Extended Cut DLC fixed that. The ending involved massive amounts of deus ex machina, completely out of the blue plot devices and, rather tellingly, didn't tell us a damn thing about the Reapers or where they came from. You had to buy a DLC for that info. It also completely ignored hanging thread plots from previous games which hinted heavily at something rather different going on, involving dark energy (which got a passing mention in the Leviathan DLC) and other such things. The ending was rushed and unclear in the message it presented, and left far too many questions for a supposed end to the trilogy.
Secondly, gameplay. While I had high hopes for the new additions to combat, the additional stealth/combat roll options, close quarter combat and enemies working as teams, the learning curve on this was not all that difficult. I can play Insanity difficulty mode and not break a sweat in most combats. It's "fake hard", which mostly involves putting more enemies on the field and having enemies with bullshit insta-kill moves (Banshees and Phantoms). I want enemies that work as actual teams, that use powers in conjunction, that apply pressure and in short act like a gamer would in their place.
Thirdly, the roleplay aspects of Mass Effect have always been overstated, and even those modest efforts were mostly stripped out in the second and third games. You don't have complete control of your character....they are a distinct person with a distinct history and distinct personality, when you pay attention. You just get to decide whether they are a goodie two shoes type, or a jerkass antihero type. Part of this is due to the limitations of a voiced main character, only so many lines can be recorded without ridiculous expenses being incurred...but part of it is simply not wanting to have to deal with a open world where more options are available.
Fourthly, the co-op gamers are frequently given preferential treatment in regards to DLC releases and similar. Co-op gets the new weapons first. Co-op gets to play with new powers which single player doesn't get. Co-op gets the new maps and enemies. I understand this is partly business motivated as much as anything, that co-op play will eventually get boring without constant new additions, but it still makes everyone who doesn't have the time or inclination to engage in co-op feel much less valued as a player, and as a consequence has created something of a rift on Bioware Social Network between those who play co-op and do not.
Some of the game was really good....great even. Mordin and Thane's deaths (lol spoiler) were pretty amazing, as was the curing of the genophage and other set pieces. But quite a lot of it, such as the N7 missions, seemed ultimately pointless. A lot of the problem stemmed from this "Prothean superweapon" nonsense, which set the tone for the rest of the game. I would have liked to have seen a war which looked, well, more like a war. Precision strikes against Reaper indoctrination facilities, being dropped behind enemy lines and causing enough damage and destruction to divert resources, the slow grind and attrition of what looks like a hopeless conflict before presenting any possible solutions.