Santos scored his first goal in the 83rd minute to break a 1-1 tie, rolling a 15-yard right-footed shot from the left side after taking a feed from Paladini and running for about 40 yards. He faked defender Jamison Olave to the turf and booted the ball past Luis Robles.
It was the first win of the season for Chicago (1-3-1), which had been held to one goal in its first four matches, totaling 360 minutes plus stoppage time.
Olave gave New York a 1-0 lead in the 17th with a left-footed volley to hammer home a header by Tim Cahill.
The Fire tied it on a header by Paladini and Santos' second goal came in the 89th minute.