Ernesto Valverde's men are sitting pretty at the top of La Liga, and has a trio of injury casualties for the visit of the struggling Merengue.
Messi is the biggest loss for the Catalans, who can stretch their lead over Madrid to seven points with victory in just the 10th game of the Liga season.
The Argentine suffered a fracture in his right arm just over a quarter of an hour into Barca's match against Sevilla, having already contributed a goal and an assist to the club's cause.
He was spotted in the stands at Camp Nou on Wednesday as his side triumphed 2-0 over Inter, and is expected to miss a total of three weeks' action as the break heals.
Samuel Umtiti (knee) and Thomas Vermaelen (hamstring) are also ruled out of the Clasico, leaving Barcelona short of defensive cover.
Barcelona do not have any players suspended for Sunday's match.
Barcelona potential starting line-up
It is likely that Valverde will keep faith with the bulk of the team that played so well in dispatching Inter midweek when the two Clasico rivals walk out at Camp Nou.
With both Umtiti and Vermaelen out, Gerard Pique and Clement Lenglet will continue as Barca's default centre-back pairing, with Sergi Roberto and Jordi Alba keeping their places out wide.
Neither are any changes expected in the midfield, as the trio of Sergio Busquets, Ivan Rakitic and Arthur gains ground as the club's strongest combination in a competitive engine room and Arturo Vidal set to continue as an option to further tax tired legs off the bench.
To the disappointment of the likes of Ousmane Dembele and Malcom, meanwhile, Barca seem to have found an alternative to Messi.
Rafinha opened the scoring against Inter and generally impressed in a rare starting opportunity, and is likely to continue in the starting XI.
With Philippe Coutinho also slated to start, the pair will lend creative support to sole striker Luis Suarez, who enjoyed a timely return to form with an all-action display against the Nerazzurri.
One alternative Valverde is mulling ahead of the game, however, would see Nelson Semedo slot in at right-back and Rafinha sacrificed, a move that would also push Sergi Roberto up to the right side of midfield in a 4-4-2 set-up.
Opta Match Facts
- No team has defeated Real Madrid more often in La Liga than Barcelona (70); while no side has beaten Barcelona more in La Liga than Real Madrid (72).
- Barcelona have scored in each of their last 21 league games against Real Madrid in La Liga (48 goals total) and could equal the best scoring record in El clásico history in the competition - Real Madrid (22 games) between 1959 and 1969.
- Real Madrid are unbeaten in their last three league games at Camp Nou (W1 D2), never in El clásico history have they managed to stay unbeaten in four consecutive games.
- Barcelona are unbeaten in each of their last 41 league games at Camp Nou in (W33 D8), their longest such run since February 1977 (67).
- Real Madrid have lost their last two La Liga games, the last time they lost three successive matches in the competition was back in May 2009 (five).
- Since his debut in El clasico, Barcelona haven’t won either of the two matches against Real Madrid without Lionel Messi in any competition (D1 L1).
- This will be the first El clásico Real Madrid will play without Cristiano Ronaldo since his move to Juventus – during his time in Madrid, Real won two games against Barcelona without the Portuguese striker, 2-1 in the 2015 Copa del Rey final and 2-0 in 2017 Spanish Supercopa.
- This will be the first El Clasico in all competitions without both Lionel Messi and Cristiano Ronaldo since December 2007, when Real Madrid won 1-0 in a La Liga match thanks to a Júlio Baptista winner.
- Barcelona’s Luis Suárez has scored six league goals against Real Madrid since his debut in the competition during the 2014/15 campaign, more than any other player in that time.
- Real Madrid captain Sergio Ramos has scored four headed goals against Barcelona in La Liga, more than against any other team in the competition.
- Barcelona manager Ernesto Valverde has lost 12 of his 20 league games against Real Madrid (W6 D2), more than against any other team in La Liga.
- Julen Lopetegui will manage in his first El clasico game - five of the last six Real Madrid managers have lost their opening match against Barcelona in all competitions - only Zinedine Zidane (2-1 at Camp Nou in April 2016) managed to win.
- Real Madrid have scored 13 goals in La Liga this season, their worst scoring record after their opening nine league games since 2004-05 (eight goals).
- Real Madrid have collected 14 points in their opening nine La Liga games, their worst record in the competition after nine games played since 2001-02 (10).
- With defeat to Levante, Julen Lopetegui equaled the worst league start of any Real Madrid manager since Juan Antonio Ipiña in 1952-53 (P9 W3 D3 L3).
TV coverage and kick-off time
Kick off is 15:15 GMT (11:15 ET) on Sunday, and will be shown on Eleven Sports 1 in the United Kingdom. It will be shown on BeIn Sports in the United States, and on various channels around the world.