Command and Conquer 4 - For the last game of a well established and well beloved series, they decide to completely scrap the gameplay and the mechanics that were in from the first game. "But Jandau!" you might say, "Change is good! Games shouldn't stagnate!". While there is SOME truth to that, it only gets worse from there - Then they proceed to replace the original gameplay with crap. Pure, undiluted crap. Poor visual design of units, simplistic mechanics, clunky controls and interface, dumbed down overall gameplay. Terrible way to send off a legend of the genre.
Napoleon:TW / Empire:TW - The Total War series started going downhill with Empire, but it was still decent. A ton of crappy design decisions, terrible coding, unfinished and buggy release and pants-on-head-retarded AI were still compensated by many positive moves, such as a better diplomacy system, revamped construction/economic system, etc. Then Napoleon shows up and guts the game, taking away the entire Macromanagement aspect of the series and leaving you with pretty much only the battles against the (still retarded) AI.
Elder Scrolls: Oblivion - Elder Scrolls were always the forerunners in Open World RPGs, with Morrowind reaching cult status. Then they put out Oblivion, a game with atrocious controls that should have been scrapped after Daggerfall, zero story, atrocious writing, terrible voice acting, moronic mechanics, a cluttered and poorly designed interface and an open world more boring than a can of spam. They did make up for it a bit with Fallout 3, but I still fear for the Elder Scrolls series...
Supreme Commander 2 - One of the more unique RTS games out there got a sequel that took every cool and original idea the first game had (or had inherited from Total Annihilation) and kicked it out, putting in completely generic RTS mechanics, ending up with a game that in no way stands out and is mediocre at best, all for the sake of getting in on the console market. I hope it was worth it.
EDIT: If you're about to quote me and tell me how awesome Oblivion is, don't bother. I understand I'm the minority on that one and let's leave it at that.