Messi collected the ball off Luis Suarez and drove it into the bottom corner in the 53rd minute at Camp Nou to give Barca a 2-0 lead over Eibar and notch his quadruple century after 435 matches.
It is 14 years since the 31-year-old Argentine scored his first La Liga goal and he has gone on to build an enormous lead at the top of the league's all-time scoring chart.
Cristiano Ronaldo remains the second highest scorer with 311 goals in 292 games while Spain's Telmo Zarra is third with 251 goals in 278 games.
Messi has finished top scorer in La Liga five times. He has 17 goals already this season.