Messi struck in either half, his second with a landmark 50th career free-kick, while defender Clement Lenglet, Arturo Vidal and Luis Suarez were also on target.
Kiko Olivas had hauled Valladolid level in the first half after Lenglet's early opener, but it was one-way traffic from there as Barca leapfrogged Granada back to the summit with a seventh straight win in all competitions.
Ernesto Valverde's side led 3-1 at half-time, while Messi curled home his free-kick in the 34th minute and also provided the assists for Vidal and Suarez.
Lucas Perez's superb late equaliser earlier in the evening earned Alaves a 1-1 draw against Atletico Madrid at the Mendizorrotza Stadium.
Former Arsenal and West Ham forward Perez fired home into the top corner from outside the penalty area in the 83rd minute to cancel out Alvaro Morata's second-half opener for Atletico.
Perez's strike denied Diego Simeone's side from briefly holding top spot and was his fifth goal in as many matches for Alaves.
Atletico currently sit third in the table after extending their unbeaten run in all competitions to 10 matches, while Alaves leapfrogged Levante into 13th place.
