The best glitches I've ever had have been in Bethesda titles. Oblivion is a common culprit and never before have I laughed so hard as with these glitches/bugs:
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I was working for the Dark Brotherhood and I had to do the mission where you sneak on the pirate ship and kill the captain. I didn't bother going in through the ship itself or the crate you and stowaway in, I had high Acrobatics and Lockpicking at the time, so I jumped on to the balcony at the back of the ship and picked the lock. I sneak in and find the captain eating, so I draw my weapon and sneak-attack-Critical-Hit him for 2/3 of his health!
I get the "NPC wants to talk" zoom-in thing and my screen is full of the back of his chair. I can only see the side of his face as he looks over his shoulder at me and says something like "Yarr, you ain't one of me mateys!" and then I exit the conversation zoom-in. At this point I'm laughing so hard I can't work the keyboard to fight him, but luckily he doesn't do a lot of damage to me. I clock him in the skull with my sword once to finish him off and leisurely stroll out the door I came in through.
The funny part for me was the "Ya think?" moment I had when I slashed his spine open and all he could say was "Yarr, you ain't one of me mateys!" (paraphrasing, again).
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Did you know that if you enchant a weapon to do 1 point of Fire damage for 1 second over 100 feet you can air combo stuff?
Learn some kind of spell that paralyzes a target and enchant a weapon in the way I just described. Paralyze something (like a bear or town guard) and hit them with your enchanted weapon. Watch them fly. Get under them and keep swinging. Watch them enter lower Earth orbit. Watch as paralysis wears off and they flail maniacally as they fall to the ground. Die laughing.
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Bribe every single guard in town so they like you at 100 Respect/Reputation/I-Like-You-This-Much-Points. Bribe to 100 your victim, whom must be someone that will fight back. Punch your victim while no one is looking so they chase you. Run up to a guard and let your victim hit you. Yield to your victim to he leaves you alone. Laugh maniacally as the town guards swarm and slay your victim for you.
I did this to most of the guild members in Bruma (both Fighters and Mages), Maglir and Oren, and the captain of the Bruma town guard. XD Yes, the town guards killed their employer.
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I know I described how to do most of these, but I guess what makes them "once in a lifetime" are all the specific things that resulted. Sometimes my victims reacted in less amusing ways and sometimes they did things completely unexpected (i.e. I did the paralysis-fire-weapon trick to a bear and I swear he flew so high he despawned). The town guard trick was pretty flimsy, especially.