Harrison lasted just one minute and 10 seconds before crumpling in a neutral corner after taking a big right from Wilder, and despite beating the count the contest was waved off by referee Terry O'Connor.
Harrison had refused to call time on his career after equally devastating early defeats to David Haye and David Price, but admitted he may now be left with no option but to bring an end to his world title quest.
Harrison said: "I think this time it is probably the end.
"There are only so many times I go knocking on doors. I've smashed those doors down in the past and shown tremendous fortitude.
"But this comeback took everything I had and I've been knocked out in the first round again.
"I will go away and think about it and talk to my family, but I don't know if I can put myself through it, or put my family through it.
"I have to accept that age the age of 41 I'm not going to get many more chances, but if it is the end I can be proud of what I've done, winning the Olympic title and the European title.
"I always said if I prepared right and came in for a fight fully focused and I was beaten then that would be it. I fought a guy with 27 knockout wins and I became number 28.
"I will go away and think about it but I think it is probably the end."
After his losses to Haye and Price, Harrison had resurrected his career yet again by winning the Prizefighter tournament in March this year, setting up his chance against 2008 Olympic bronze medallist Wilder.
But he was clearly no match for the American, who had compiled his impressive 27-fight knockout record entirely against American also-rans, but looks ready to stake a serious claim to move into the world title picture.
As usual Harrison's entry to the ring was greeted with a mixed reception, while the lanky Wilder looked serious and focused ahead of his British debut.
After a brief opening exchange in which Harrison almost landed with a neat left hook, Wilder pounced, using his strength to bull the former Olympic gold medallist back before unleashing the right hand that marked the beginning of the end of his high-profile career.