Nicolas Zigic scored a penalty in the 56th minute to give the leadership of Santander in El Sardinero stadium, but from Argentina scored their first point in the 65th, slotting in a loose ball in the next post .Messi then go chested a ball toward the right side of the area before volleying a right-footed shot on goal and beyond the goalkeeper Antonio Rodriguez to a 81st-minute winner Barcelona stretched the unbeaten league run to 20 games.
Barcelona leads with 56 points from 21 games, Real Madrid is second with 44 and Sevilla has 38.
Raul Gonzalez Alfredo di Stefano joined Madrid as an all-time leading scorer when they hit the winner for the Spanish champions in a 2-0 win at Numancia on Saturday.
Coach Javier Aguirre's job could be in line after Atletico remains winless in 2009 after a 2-1 loss to Valladolid.
In yesterday's other games, it was: Espanyol 1, Recreativo Huelva 1, Real Betis 2, Getafe 2, Deportivo La Coruna 3, Villarreal 0; Osasuna 1, Mallorca 0; Valencia 3, Almeria 2, Sporting Gijon 1, Sevilla 0 .
Barcelona controlled the midfield play, but not to turn their possession into opportunities within the target area, like Messi, seen from the dock.
Center back Rafael Marquez returned from injury to replace Barcelona captain Carles Puyol, who is with a muscle strain.
Racing physical game keeps Barcelona at bay with Sergio Busquets mistreated at the edge of the area in the 45th to deny a break in Barcelona.
Santander first broke the penalty spot after Marquez was booked for taking down Jonathan Pereiro inside the area. Zigic scoring the penalty for his fourth goal in as many games since joining from Valencia.
Busquets Messi became the 60th just after the Catalans were lucky not to lose Daniel Alves, forcing Toni Moral from the game with an ankle-high challenge. Brazil again was not booked.
Xavi Hernandez, by Thierry Henry off the cross bar and Messi was there to slot the rebound with his first touch.
Barcelona Messi then sealed the ninth straight win with his 16th goal of the season - the second highest in the league behind Samuel Eto'o team.
Barcelona finished with nine after Marquez picked up a second booking in the 88th, while Gerard Pique was sent off in injury time for a second yellow.
Athletic Bilbao twice from a goal deficit to beat Malaga 3-2 on Saturday.