The five-time World Player of the Year struck either side of Carlos Castro's well-worked equaliser in a three-goal burst in five first-half minutes.
Luis Suarez missed a second-half penalty days after famously converting Messi's pass from a spot-kick against Celta Vigo, but made amends with a brilliant finish for Barca's third midway through the second half.
Atletico Madrid are Barca's closest challengers with Real Madrid a further point adrift in third.
The match had been postponed due to Barcelona's commitments in the Club World Cup in December and, with a huge clash against fellow strugglers Real Betis to come on Saturday, Sporting boss and former Barca defender Abelardo Fernandez made nine changes to his side from the team that started Friday's 2-2 draw with Rayo Vallecano.
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Barca coach Luis Enrique also made five changes, but the star front three of Messi, Suarez and Neymar started after their incredible display in the 6-1 thrashing of Celta at the weekend.
Suarez had the first chance to extend his lead as the league's top scorer from Neymar's inch-perfect pass, but the Uruguayan fired straight at Ivan Cuellar.
Messi broke the deadlock with a deadly accurate drive into the bottom corner from 25 yards to become the first player ever to bring up a triple century of La Liga goals.
Barca promptly responded, though, as Suarez showed great strength to hold the ball up and then lay it off for Messi to fire into the roof of the net with the outside of his left foot.