Napoli, who wielded a hot bat for Texas in a seven-game series loss to the Cardinals in 2011, struck the key blow against the same opponents in a first-inning outburst that helped the Red Sox ease to an 8-1 victory.
The first baseman now has two doubles, two home runs and 13 RBIs in eight career World Series games.
"I love this stage," Napoli told reporters. "It's in the spotlight. I really enjoy this time of year, I guess."
Napoli said coming through in the clutch was especially sweet against St Louis.
"I think it's nice being able to play against them," he said. "They took a world championship away from me."
Napoli got his opportunity after an unusual turn of events on a routine grounder hit by slugger David Ortiz with men on first and second and one out that ended up leaving the bases loaded for the Red Sox first baseman.
Matt Carpenter gathered the Ortiz grounder and tossed the ball to shortstop Pete Kozma covering second in the hope of triggering an inning-ending double play.
The ball fell to the ground but second base umpire Dana DeMuth still called the base-runner out, ruling that Kozma had lost control of the ball when transferring it from his glove to throwing hand.
Television replays, however, showed Kozma did not catch the ball and it had grazed off the tip of his glove.
With more extensive official video replays not coming into effect until next season, such on-field calls have generally stood.
But after protests from Boston manager John Farrell, the six umpires on duty conferred and surprisingly reversed the call and Kozma was tagged with an error that loaded the bases.
The shock ruling lit up the Fenway Park crowd, who roared in anticipation when Napoli came to bat, and he delivered with a rocket to left-center that cleared the bases for a 3-0 lead.
"To their credit, they did confer, and I think the one thing is we just strive to get the call correct," Farrell said. "Surprisingly, to a certain extent, they overturned it and I think got the call right."
"It is a pretty big swing moment."
St Louis manager Mike Matheny was frustrated by the turn of events.
"What was explained was they wanted to get the call right," Matheny said. "And they got together as a group, and five of them believed that the call was different than the one that was made."
"That's not a play I've ever seen before," he added. "It's a pretty tough time to debut that overruled call in the World Series. Now, I get that, trying to get the right call, I get that. Tough one to swallow."