The Pacific islanders were bright from the off in the November international and Fa'atoina Autagavaia scored a try after just over a minute following a flowing drive marked by missed Wales tackles.
The hosts went in 13-10 ahead at the break, albeit against the run of play thanks to Ashley Beck's breakaway try after an interception well inside his own half.
Wales started with usual captain Sam Warburton on the bench and with Mike Phillips recalled as scrum-half but eight changes from the defeat by Argentina last weekend failed to spark the home side under interim coach Rob Howley.
The Welsh, who host the All Blacks next Saturday when coach Warren Gatland returns from British and Irish Lions' duties, clung on after the break thanks to the boot of Leigh Halfpenny.
However, an early second-half try from George Pisi and Johnny Leota's late touchdown sealed a deserved victory for the Samoans.
Wales, on a high after March's grand slam triumph, lost all three tests in Australia in June before going down to Argentina and Samoa in a stark reminder to the Six Nations sides of how far behind the southern hemisphere they have fallen.
In Warburton's absence, former skipper Ryan Jones took over the armband for a record 29th time but was far from happy.
"What could have been the greatest day of my career has turned into one of the worst," he said.
"We came second best in quite a few facets of that game. It was a game that slowly slipped away from us and we didn't have enough in the end.
"But that's not taking anything away from Samoa, who turned up with a physical edge and a gameplan that stopped us playing again."
Samoa, who also beat Wales in the 1999 World Cup when their more celebrated opponents were hosts, travels to France next Saturday seeking another scalp.
Wales fly half Rhys Priestland was also dropped to the bench but was called into action amid a raft of Wales injuries during the game, which did not help the hosts' cause.
"They got some big boys, physical boys," Priestland said when asked about Samoa.
"It's going to be tough (against New Zealand). It's the toughest match in world rugby. We've got some injuries. We've got to look in the mirror."