Querrey, the runner-up at the 2009 Newport event, was upended by Smyczek 6-4, 7-6 (10-8) at the International Tennis Hall of Fame and Museum.
The news was better for fourth-seeded 2012 runner-up Lleyton Hewitt, however, as the Australian overmatched compatriot Matthew Ebden 6-4, 6-1.
Hewitt fell in last year's final to two-time defending champ John Isner, seeded second in this year's edition.
Also advancing to the second round Tuesday were No. 2 seed Igor Sijsling of the Netherlands, who dispatched Italian Matteo Viola 6-4, 6-1, and eighth-seeded American Rajeev Ram, who breezed past Swiss qualifier Adrien Bossel 6-2, 6-2.
Elsewhere at Newport, fifth-seeded Frenchman Edouard Roger- Vasselin was upended by Croatia's Ivo Karlovic and American Jack Sock downed sixth-seeded Australian Marinko Matosevic, 6-2, retired.
Americans Michael Russell and Alex Kuzentsov, France's Nicolas Mahut, Indian wild card Prakash Amritraj, Canadian Vasek Pospisil and Czech Jan Hernych also moved into the second round with Tuesday victories.
Swim Week Miami Beach 2014 [PHOTOS]