Connacht's Tiernan O'Halloran and Quinn Roux also started for Ireland as man-of-the-match Keith Earls scored two tries and had three assists.
Joe Schmidt fielded a team mixed with experience but mostly youth, as 21-year-old pair Jacob Stockdale and James Ryan enjoyed try-scoring debuts Stateside and Heffernan, Andrew Porter and Rory Scannell also won their first caps.
It was a night of firsts at a very humid Red Bull Arena where Rhys Ruddock captained Ireland for the first time, becoming the country's 105th captain at Test level, and Stockdale, Ryan, Niall Scannell, Jack Conan and Luke McGrath all claimed their maiden international tries.
A brace from the electric Earls - taking his Ireland tally to 24 tries and seven for this season alone - helped the visitors lead 29-7 at half-time, the only real blip being American lock Nick Civetta's try after charging down Joey Carbery.
Young out-half Carbery, who struggled off the tee on his first start, fell into the same trap in the second half when former Dolphin favourite John Quill blocked his attempted clearance for another softly conceded try. Centre Ryan Matyas' subsequent score was very much the Eagles' own work, but Ireland responded with three closing tries from replacements Ryan, McGrath and Zebo to run out convincing winners.
It was the highest score Ireland have put up against the USA in their last four meetings, and speaking afterwards, head coach Schmidt gave the nine-try performance 'a pass mark' while also providing an update on the injury that Carbery sustained.
"It's a pass mark, first up. This group has worked hard but it's always difficult to put it together. The US got into our space really well and made us work hard. I thought they got into our space quite a few times," he said.
"Particularly Joey, they got into the space with his cross kicks because they were up and in at us. It was oppressively hot out there and heavy for the players. The other thing at half-time that the lads were saying was the ball was incredibly slippery.
"There was a lot of perspiration on the ball which made it incredibly hard to get long transfers. Shorter transfers were okay but as soon as you wanted to try to get enough bite on the ball to get it wide, it was a little bit difficult.
"Joey sprained his ankle a bit chasing across the pitch. He just went to turn back. We thought it pertinent to get him off. We don't know what the story is yet. It hasn't really swelled too much but it was a bit tender so we'll see how it settles and maybe get a scan, either here or once we've arrived in Tokyo (for the next part of the tour)."
The 30-degree heat had some jerseys dabbed with sweat before kick-off, a lively opening spell seeing both out-halves hand possession to the opposition from attempted chips. America's early pressure was broken up by the penalty-winning breakdown efforts of Josh van der Flier and Cian Healy - now Ireland's most-capped loosehead prop thanks to his 68th cap.
The game was only two-and-a-half minutes' old when Tiernan O'Halloran shrugged off a poor tackle, drew the final defender and passed for Earls to comfortably finish in the right corner. Carbery was unable to convert from out wide.
The USA had plenty of early possession but nothing to show for it after turning down a kickable penalty. Ireland looked much more threatening off limited ball, although a Conan-inspired break should have had a better outcome than an O'Halloran kick that slithered into touch.
Nonetheless, the Irish attack clicked on the quarter hour mark when Carbery's inside pass sent Earls scurrying through midfield and the Limerick man lofted a terrific pass out to the left for the waiting Stockdale who gleefully made it over in the corner. Garry Ringrose, who was heavily involved in the visitors' early defensive stand, nailed a top class conversion.
Earls, who was a regular threat out wide, made it three tries inside 18 minutes when O'Halloran countered expertly from the American 10-metre line, profiting from another missed tackle as he linked with Earls who gathered Marmion's return pass to nip over by the right corner flag.
Carbery could not convert and blundered from the restart as his attempted chip was blocked by Civeta and the lock's opportunist score was converted by former Connacht number 10 AJ MacGinty for 17-7.
The sturdy Stockdale was hard to put down as he thoroughly tested the Eagles' tackling, while Ireland's scrum was making inroads as the minutes ticked by. Hooker Niall Scannell was also catching the eye, throwing steadily at the lineout and twice making good yards as a carrier.
Discipline around the ruck was an issue for the USA, a series of penalties inviting Ireland forward and off a Quinn Roux lineout take, the maul powered through for Scannell to plunge over with 31 minutes on the clock. Carbery struck the left hand post with his conversion kick.
Outfoxing the home defence from a 34th minute scrum, Marmion started and finished a slick two-man attack up the right wing for Ireland's fourth try. The Connacht scrum half scampered up the blindside, fed Earls and took the tackled winger's pop off the deck to weave inside the final two defenders for a superb seven-pointer. Carbery found his range to add the extras.
Munster's Rory Scannell joined his brother on the pitch for the start of the second half, with Ireland armed with a 22-point lead. Having blown a maul opportunity, the Ireland forwards redeemed the situation with a powerful scrum shove in the 44th minute and number 8 Conan dribbled through for a well-taken try which Carbery converted with his best kick of the night.
However, there was a sense of déjà vu when the Ireland number 10, standing flat to a ruck, had another kick blocked by Corkman Quill who was thrilled to touch down against the country of his birth. MacGinty converted and it was his show-and-go and subsequent touchfinder that kept his side playing in the right areas.
The Cork contingent on the field increased with prop Paddy Ryan, a brother of former Munster front rowers Timmy and Dave, coming on to make his USA debut. Unfortunately Carbery went the other way, hobbling off to be replaced by Simon Zebo. Rory Scannell switched in to out-half and Earls went to outside centre.
Both benches began to unload with half-an-hour remaining, Test newcomers Porter and Heffernan linking up with Dave Kilcoyne in an all-new front row combination. A couple of set piece penalties allowed the Eagles to suddenly lift the tempo, getting to within metres of the whitewash before Matyas managed to nip over on the right.
That proved to be the Americans' last score of the night, though, as Ireland gradually regained their poise to post three tries during the final quarter. John Mitchell's charges made it a hard grind with Joe Taufete'e stealing a ruck ball close to his own line, Ringrose double-teamed and denied a try, and then the Irish forwards were held up.
Replacement Ryan became the second member of last year's Ireland U-20 team to get on the scoresheet, following up another slashing run from Earls to bag a try with only his second touch at this level. Scannell's conversion bounced away off the post but he was bang on target in the 69th minute, supplying the extras to McGrath's sidestepping snipe from the back of a ruck.
A timely injection of power and pace into Ireland's game, with Conan, Kilcoyne and Heffernan all carrying strongly, saw them wrestle back control of the game, albeit that Heffernan and his jumpers still had lineout issues to iron out. Ireland's defence continued to be tested with McGrath putting in a try-saving tackle on American skipper Nate Augspurger.
A couple of box-kicks from McGrath, with Conan fielding the first one and the second leading to an Irish lineout up in the 22, paved the way for the ninth and final try. Stockdale was first to reach Scannell's high, hanging cross-field kick, knocking it back for the supporting Zebo to ground the ball. Scannell's curling conversion made it a 36-point winning margin in the end.