Reigning champions Barca lead their arch rivals by a point with two matches left and play at Champions League hopefuls Sevilla, in fourth, while Real host Athletic Bilbao, who are eighth and bidding for a Europa League berth.
Ronaldo's hat-trick against Real Mallorca on Wednesday put the Portuguese third on the La Liga scoring chart with 25, one behind team mate Gonzalo Higuain, and Argentine Messi leads on 31 after his double against Tenerife on Tuesday.
Ronaldo became the world's most expensive player when he joined Real from Manchester United for around 94 million euros at the end of last season, while Messi has been at Barca since the age of 13.
A Barca victory in Sevilla and a slip-up by Real at home to Bilbao will guarantee Pep Guardiola's side a second straight title as they won both this season's "Clasicos" and head-to-head record separates sides if they are level on points.
Barca's total of 93 from 36 matches is a record, surpassing the 92 accumulated by Real under Fabio Capello in the 1996-97 season when there were 22 teams rather than 20.
"Let's hope Sevilla can take points off them, but our fate is not in our own hands," Real coach Manuel Pellegrini said at a news conference after the 4-1 win in Mallorca.
"Our obligation is to get to 98 points and we'll see if Barca can get to 99."
Five teams are deep in relegation trouble, with promoted Xerez hanging on by a technical thread after their 3-1 defeat at Valencia on Tuesday.
Tiny Xerez, who have an annual budget around 40 times smaller than Real and Barca, are bottom on 30 points and their superior head-to-head record over Malaga is the only thing that is saving them from going straight back down.
Racing Santander are in 17th on 36, one point above the relegation places and the same tally as Malaga in 16th, who have a superior head-to-head record. Tenerife are 18th on 35 and Real Valladolid are 19th with 33.
In Saturday's games, which are all at 7pm GMT, Xerez host Real Zaragoza, Racing travel to Valladolid, Malaga play at Getafe and Tenerife host Almeria.
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