Valencia currently occupy seventh spot in the table with 31 points to show from their 20 matches, while Barca still lead second-placed Real Madrid by goal difference at the top of the division.
Having claimed back-to-back fourth-place finishes in La Liga, it would perhaps be fair to say that anything other than securing a Champions League spot for next season would go down as a disappointment for Valencia this term.
It has been a tough campaign for Albert Celades's team, though, with inconsistency very much an issue. A record of eight wins, seven draws and five defeats has left them in seventh spot in the table, but they are only four points off third-placed Atletico Madrid heading into week 21.
Los Che have lost two of their last three matches, though, including a heavy 4-1 loss at Mallorca in the league last weekend. They did return to winning ways in the Copa del Rey on Wednesday night but now face an incredibly difficult clash against the reigning champions.
Valencia have not lost on home soil in the league since April, though, and have won three of their last four in front of their own supporters, in addition to holding Real Madrid to a 1-1 draw in December.
Somewhat surprisingly, Valencia have not actually beaten Barca in the league since April 2016, while they have not recorded a home league success over the Catalan giants since February 2007.
Barca were also in Copa del Rey action on Wednesday night and secured their passage into the round of 16 courtesy of a 2-1 win away to Ibiza. It was actually a tough 90 minutes for the Spanish champions, but they progressed courtesy of a late Antoine Griezmann effort.
As a result, the Catalan giants are still top of the table with 43 points from their 20 matches, but Real Madrid are only in second on goal difference and will fancy their chances of beating Real Valladolid on Sunday.
It certainly does not appear that Barca will be running away with the league this season, and they have actually been held by Real Sociedad and Espanyol in their last two La Liga fixtures on the road.
As mentioned, the team's recent record against Valencia is strong, although three of their last four league matches at the Mestalla have finished with the two sides sharing the spoils.
Valencia La Liga form: WWDDWL
Valencia form (all competitions): DDWLLW
Barcelona La Liga form: WDDWDW
Barcelona form (all competitions): DWDLWW
Valencia will again be without the services of Cristiano Piccini, Goncalo Guedes and Manu Vallejo through injury, but key forward Rodrigo Moreno is being tipped to recover from a knee problem to feature.
Messi was not involved against Ibiza but will return to the XI here, and Setien could well select a 3-5-2 formation once again with Griezmann partnering the returning Argentine in attack.
Valencia possible starting lineup:
Domenech; Wass, Paulista, Diakhaby, Gaya; Cheryshev, Kondogbia, Coquelin, Soler; Rodrigo, Gameiro
Barcelona possible starting lineup:
Ter Stegen; Lenglet, Umtiti, Pique; Roberto, Busquets, De Jong, Rakitic, Alba; Griezmann, Messi
We say: Valencia 1-2 Barcelona
There is no question that Valencia are capable of making it a very uncomfortable match for Barca, but Griezmann's double against Ibiza during the week would have handed him confidence, and the fact that Messi was given the night off means that the Argentine should be fresh. We fancy the champions to put what would be a huge three points on the board courtesy of a narrow win.