Isner found himself a set down against Colombian qualifier Santiago Giraldo before winning 4-6 7-5 7-5 in the first round.
The 14th seed had to contend with a typhoon, playing under the closed roof at the Qizhong tennis centre, but threw in numerous errors. Typhoon Fitow battered China's east coast on Monday.
Isner dropped the first set before restoring parity on his seventh set point in the second. Isner came up with 29 aces but threw in 32 unforced errors. He broke Giraldo in the 12th game of the third set to seal victory.
Elsewhere, Spain's Marcel Granollers won 6-4 6-4 against Serbian Janko Tipsarevic, a figure who toiled with problems to his left ankle .
Fifth seed Roger Federer, who trained in intense heat in Dubai before coming to Shanghai, opted not to play a competitive match for over a month following his loss to Tommy Robredo at the US Open.
But much to the delight of the local crowd, he partnered local hero Zhang Ze, ranked 271 in singles and 437 in doubles, to breeze past Kevin Anderson and Dmitry Tursunov 6-2 6-1 to record his first doubles win of 2013.
Latest results from the Shanghai Masters Men's Singles Round 1 matches on Monday
11-Tommy Haas (Germany) beat Sam Querrey (US) 6-4 6-4
14-John Isner (U.S.) beat Santiago Giraldo (Colombia) 4-6 7-5 7-5
Gael Monfils (France) beat Tatsuma Ito (Japan) 6-3 6-2
Marcel Granollers (Spain) beat Janko Tipsarevic (Serbia) 6-4 6-4