After his side's magnificent triumph over world champion New Zealand last weekend, Schmidt made 14 alterations for Ireland's final Test of 2018, with Garry Ringrose the only player retained.
The Six Nations champion was put under pressure early on by USA, whose own form coming into this match had also been impressive, albeit against more limited opposition
Yet the gulf in class between the two teams soon became apparent as the game wore on, with Ireland racking up 43 unanswered points after it was pegged back to 14-14 in the first half.
Conway claimed each of his side's first two tries, only for those scores to be cancelled out by Joe Taufete'e and a United States penalty try, the latter score coming as Iain Henderson was sin-binned for bringing down a maul illegally.
A penalty from Joey Carbery, who converted seven of Ireland's eight touchdowns, edged the host back in front and Jack Conan extended that lead before half-time.
USA was thoroughly outclassed in the second period, with Conway completing his hat-trick and Tadhg Beirne, Stuart McCloskey, Quinn Roux and John Ryan also going over.