Having started the final day 9-6 ahead, Team USA extended their lead to four at Alexandra Palace.
In a race to 11, Team Europe began to fight back and won three in a row after victories from Jayson Shaw, Niels Fiejen and Eklent Kaci.
But Shane van Boening got the decisive point for Team USA, beating Alex Kazakis 5-3.
Van Boening won a tense encounter by hitting the 1 ball onto the 9 to pocket the trophy.
It led to wild celebrations with Team USA players jumping on the table as they ended an eight-year Team Europe streak.
Johan Ruijsink captained Team USA to success having previously led the Europeans to seven successive Mosconi Cup titles.
He last captained Team Europe at Blackpool in 2014 when they ran out comfortable 11-5 winners.
But after a brief retirement from the competition, Ruijsink returned in 2017.
And he was delighted to get his hands back on the famous trophy.
“It’s completely different, it’s been more than hard work this year,” Ruijsink told Sky Sports.
“Team Europe battled so hard and made it really tough on the last day.
“Everybody made a lot of sacrifices and now it’s just amazing.
“We are a team, we are committed and we worked hard.”