Hat-trick number seven came just over a month after number six as Messi went on to score 10 goals in the 2016-17 group stages, brushing aside Pep Guardiola's Man City side at the Nou Camp.
They moved through the gears after the restart but found PSV dogged in defence, with two further excellent goals needed to make the points safe.
The 31-year-old opened the scoring against PSV and then added another two to complete his hat-trick after Ousmane Dembele had doubled Barcelona's lead.
Dembele was fouled by Nick Viergever and Messi nonchalantly curled the ball into the top-right corner beyond a helpless Jeroen Zoet.
"When he stops playing it will be hard to find someone like him. I know they will ask him for the shirt, but they shouldn't do it at halftime".
"He has an incredible left foot", Ivan Rakitic said. "I hope he goes on like this forever and scores many more goals", the midfielder told reporters after the game, via Sport. We can still get better. He is behind CR7, who has 120 goals.
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Even PSV coach Mark van Bommel lauded the five-times world player of the year, saying: "For me he is the best player in the world".
Top seeds Barcelona are favourites to progress in a quartet that also features Tottenham Hotspur and Inter Milan.
Regarded by many as the greatest footballer of our generation, arguably, Messi has done things on the pitch that other footballers can only dream of, if not execute on a video game.
The Camp Nou will be the base of the Blaugrana's success in Europe this season as Ernesto Valverde looks to put a stop to Real Madrid's stranglehold over the Champions League and tonight they were emphatic at the Camp Nou, brushing past PSV with relative comfort.
If the World Cup proved anything, however, it is that Messi can not do it alone and Barcelona Messi will need others to shine if they are to end their Champions League hiatus.
And Rakitic is aware of the challenges that await in the competition as he acknowledged the need for his side to keep improving on their win over PSV if they are to come out victorious in the Spanish capital come May.