Most of the posts on this website make me facepalm.
But aside from that, perhaps the most effective defense against this is to carry a gun and use it, like that father of the 6 year old girl who shot the boy who tried knocking him out.
Bernard Goetz had the right idea.
And, if you don't know what you're doing -- you've got a damn good chance of finding yourself tried and likely convicted of manslaughter or worse.
I don't have the link to someone who said it better than I can handy, so this my own paraphrase & take on it.
I would say that the so-called knockout game is a form of Group Monkey Dance crossing with a Status Seeking Show. It's an action by one individual within a group to cement or secure status but being urged by the group. There is ALWAYS a group; otherwise it's outright ambush attack and they're going to knock your *** out and take whatever it is they're after. Be aware of group dynamics around you. If you see the signs of the group splitting out -- do something. And don't be prey; be alert, paying attention to your surroundings. That's stuff that's been harped on ad nauseum.
Physical self defense really only comes into play after your hit. In the case of the knockout game -- it's OVER with the hit, and the jerkwad (because I want it to pass the filter) is on the way back to his buddies. You chase him and even simply grab him, and what have you done? You've committed an assault yourself, because you just grabbed some guy who was no longer presenting a threat! Shoot him? What justifies lethal force against him at that moment? I sure hope you've got a real good self defense attorney on speed dial, 'cause you're probably gonna need their help.
So... with that strong caveat... how do you respond if you missed the clues and get hit? Rory Miller has some good counter ambush stuff in Facing Violence, and if you're lucky enough to get to work with him at one of his Ambushes & Thugs seminars. Tony Blauer's SPEAR method works, too, for some folks. Or lots of the other flinch response stuff... The common pattern? Use classical conditioning to build a response that lets you recover from the initial blitz "instinctively" until you can respond more rationally.
Actually... I just remembered where I saw it and who wrote it. Don Roley's blog.
A few things distresses me about the comments and such I see on facebook, etc. Many martial artists seem to think that their training will save them from this type of thing. Many gun enthusiasts seem to drool over the idea of these animals trying the game on a person carrying a concealed firearm. Well, none of that will save you from being surprised and knocked out before you ever realize there was a threat. Some self defense mavens have tossed the word "awareness" around, but none really seem to detail the specific type of skills of awareness needed in this case. I will try to do that here.
But before I do that, let me point out to those that are looking for a fight or an excuse to shoot someone over this- know the legal situation. In most places in the world, you are allowed to use force ONLY when you are being attacked. In some places, I know that you can get away with using force when facing an attack but have not yet been attacked. It is a tricky call. If someone leans in to you at a bar and says, "I am going to take this knife out of my pocket and rip your throat out with it", in some places you would get prosecuted for taking the initiative and hitting them before they can pull it out. In others, if you could prove they threatened to kill you like that you would be justified in what you did. It is not a matter of just the law, but who is on the bench and in office.