After putting his first goal past Chelsea in a 1-1 draw in the Champions League on Tuesday, Messi brought the list of sides he has failed to score against in his career down to 10 against the Spanish side on Saturday.
Girona took a a surprise early lead at Camp Nou, but Messi was on hand to help pull his side level two minutes later when he set up Luis Suarez to record his 148th assist in the Spanish top flight, a new all-time high.
At the half hour mark, Suarez returned the favour as the Argentine got his first goal against their Catalan neighbours in two attempts.
The 30-year-old appeared to have missed his chance to beat Girona goalkeeper Bono when he tried to switch to his left foot and was crowded by defenders, but he managed to make the space for his shot.
Messi then went on to score another one six minutes later, sending a free kick under the wall and beyond Bono before playing a key in the build up to Suarez's second of the game as Barca held a 4-1 lead at half-time.
A Philippe Coutinho strike in the second half ran the score to 5-1.
36 - Lionel Messi has now scored against more different teams than any other player in La Liga history, surpassing Raul Gonzalez and Aritz Aduriz (35). Genie. pic.twitter.com/zjEPCuHAVU— OptaJose (@OptaJose) February 24, 2018
Suarez rounded out his hat-trick with a nice finish in the 77th minute as the league leaders rolled to a 6-1 win.