The Primera Division leaders take on second-placed Atletico Madrid on Sunday, with Messi and Atletico's own hot-shot Radamel Falcao both likely to be on show at the Nou Camp.
Messi and Falcao have 39 league goals between them already this season with the former breaking Gerd Muller's all-time record for the number of goals in a calendar year, previously 85, in Barcelona's win at Real Betis last weekend.
Meanwhile Falcao, who missed training with a muscle injury on Thursday but is expected to play from the start on Sunday, smashed five goals in Atletico's 6-0 hammering of Deportivo on the same evening.
But it is the continuing goalscoring exploits of Messi, who has moved three ahead of Muller after netting twice against Betis and twice again in the cup win over Cordoba, which set him apart from the rest according to Mascherano.
"Messi is unique because he is already the best player in the history of this sport," Mascherano said. "We are talking about 88 goals as if it were something normal but what he has done is incredible. This is a lad who has been touched by a magic wand."
But the top-of-the-table clash is not just about the two main goalscoring protagonists as Barcelona look to extend their lead at the top of the table to nine points with a win over Atletico.
Arch rivals Real Madrid are already 11 points adrift but Barcelona midfielder Xavi is not ruling either of the Madrid giants out of the title hunt.
"Atletico Madrid are rivals and have not given up after they lost to Madrid, far from it," he said. "It is increasingly difficult to win - Madrid can overcome many things and it is far too early to predict anything and start speculating."
Madrid also play Sunday night when they host Espanyol at the Bernabeu, with the visitors languishing in 19th place in the table and with only one away win in the league so far this season.
Ernesto Valverde has won his first two games as coach of Valencia and will look to keep the improvement going against Rayo Vallecano at the Mestalla, while Sunday's other game sees Real Zaragoza take on Levante.
Malaga reached the knockout rounds of the Champions League as group winners and stand fourth in the Primera Division, on course for top-level European football again next season.
They travel to Sevilla on Saturday, with seventh-placed Getafe, only two points behind Malaga in the table, hosting Osasuna.
Elsewhere on Saturday two of the league's struggling sides will be looking to pull away from the relegation zone.
Granada, who occupy 18th place, host Real Sociedad while 17th-placed Real Mallorca take on Athletic Bilbao.
Bottom side Deportivo play on Monday when they host eighth-placed Real Valladolid, with Real Betis travelling to Celta Vigo on the same night.