Isner, ranked 12th, could not break the serve of seventh seed Sock, as the rising star downed his fellow American 6-4 7-6 (7-4) in one hour and 28 minutes.
Sock came into the ATP 250 tournament in Rhode Island on the back of winning the Wimbledon men's doubles title (with Vasek Pospisil), and he has transferred his grass-court form across to the singles format.
The result marks a maiden tour-level semi-final appearance for the 76th-ranked Sock, and he will meet Australian veteran Lleyton Hewitt in the last four.
Hewitt, the third seed in Newport, cruised to a 6-4 6-4 victory over American sixth seed Steve Johnson.
The 33-year-old continued his love affair with the US grass-court tournament, as he moved within one win of reaching the final for a third consecutive year.
The Australian broke in the fifth game, which was all he needed to wrap up the first set.
Johnson broke serve first in the fourth game of the second set to open up a 3-1 lead, however Hewitt broke twice in succession to reel off four straight games before serving out the match.
Hewitt, ranked 43rd, and Sock have never played on tour.
The other semi-final is between Hewitt's compatriot Samuel Groth and Croatian second seed Ivo Karlovic.