Inter midfielder Joao Mario went down on the edge of the penalty area under a challenge from Francesco Vicari in the 22nd minute and referee Claudio Gavillucci quickly called for the video replay.
After a lengthy consultation, the official finally awarded a penalty and Inter captain Mauro Icardi sent Alfred Gomis the wrong way for his fifth goal in three games, officially recorded as being scored in the 27th minute.
Ivan Perisic completed Inter's win with a thumping volley in the 87th minute to leave his side with nine points from their opening three games and hand SPAL a first defeat of the season.
In between, Milan Skriniar crashed a long-range effort against the crossbar after spotting Gomis off his line.
SPAL, who have returned to the top flight after a 49-year absence, were far from outclassed and created several dangerous situations.
Serie A is one of several national leagues trialling the VAR system before soccer's rule-making body IFAB decides whether to permit their use on a permanent basis.
FIFA are hoping to use VARs at next year's World Cup.
(Writing by Brian Homewood; Editing by Toby Davis)
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