USA ended a three-game winless run in fine fashion, dominating Guyana for the most part in the Group D clash at Allianz Field in Minnesota.
Paul Arriola opened the scoring in the 28th minute before a Tyler Boyd brace and Gyasi Zardes goal in the second half.
Having been under some pressure after struggles in friendlies, it was the ideal start for the defending champions as they joined Panama on three points in the group.
Christian Pulisic was particularly bright down the left early for USA, who while dominant took time to create clear-cut chances.
Boyd fired a chance wide in the 18th minute, while Pulisic was denied by a good save from Guyana goalkeeper Akel Clarke.
But USA found a deserved opener through Arriola in the 28th minute.
Weston McKennie did brilliantly down the left before passing inside to Arriola, who curled an effort past Clarke and into the far corner from inside the area.
Pulisic almost teed up Nick Lima for USA's second, but the full-back's strike was well saved by Clarke after a pass from the attacker.
USA should have gone into the break with a 2-0 lead, however Pulisic made poor connection with a header from a Lima cross at the back post on the stroke of half-time.
But Boyd's first international goal would double USA's lead six minutes into the second half.
Michael Bradley's pass found Boyd, who took an excellent first touch before powering an angled finish into the bottom corner for USA's 1,000th goal.
Zardes was fortunate to add to USA's lead, Arriola's powerful strike partially cleared by a defender into the forward's face and into the back of the net.
USA were in control from then on, although McKennie came off with a suspected hamstring injury.
Boyd completed his brace in the 81st minute, taking a pass from Arriola before his 20-yard strike took a deflection and beat Clarke.