The 2014 U.S. Open champion moved well throughout the nearly three-hour match and appeared unhindered by the adductor injury and foot blisters that ailed him during his straight sets loss to Roger Federer at the All England Club.
"I feel just a little bit rusty," fifth seed Cilic said in an on-court interview after the match. "I need a few matches to get in the rhythm. I was hitting some good shots and then making some unforced errors."
Cilic ended with 57 unforced errors, many coming from his wobbly forehand, compared to 55 winners.
Sandgren, playing in just his second main draw of a grand slam, was composed throughout the match but appeared to tire as the match wore on.
The 26-year-old American was ultimately unable to overcome the early deficit and Cilic's powerful serve and punishing groundstrokes.
"Tennys was fighting quite hard even after I was up two sets to love. The fourth set was a battle, especially the game at 4-3."
Sandgren sent a shot wide to hand Cilic a break and end the over 10-minute game.
Cilic cracked his 11th ace to win the match in the next game and punch his ticket to the second round.
Next up for Cilic in the second round is German Florian Mayer, a 7-5 0-6 6-3 6-4 winner over Brazil's Rogerio Dutra Silva.
(Reporting by Rory Carroll; Editing by Frank Pingue)
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