The ex-Liverpool manager may field a much-changed side, but will be keen to avoid an upset in the first leg at the Estadio Ramon de Carranza.
Real sporting director Emilio Butragueno has fond memories of previous visits to the Cadiz and has praised the club's "great tradition and extremely passionate supporters".
El Buitre has other reasons for relishing his trip to the Ramon de Carranza, as it is here he was given his first big break in La Real's second team, under the tutelage of Madrid great Alfredo di Stefano.
However, the Yellow Submarine have not backed up their great tradition with great success in recent years and, since the days when El Salvador forward Magico Gonzalez entertained the crowds on the South Coast in the early 1990s, Cadiz have played only one season in the Primera Division.
That came after winning the Segunda title in 2005, but they would finish second from bottom and then dropped into the Segunda B in 2008. Cadiz briefly regained their status in the second tier, only to suffer relegation during their first year back in the division.
Claudio Barragan's side do have some pedigree in terms of testing top-flight opposition, having held Atletico Madrid to a goalless draw in pre-season, although they did lose 5-1 on aggregate to Villarreal in last year's Copa at the same stage.
The Yellow Submarine are unbeaten in their last six league matches (three draws and three victories), including a 1-0 win over Almeria B on Saturday.
Recent form (all competitions): DWDWDW
In the wake of the 4-0 home defeat at the hands of bitter rivals Barcelona, Benitez has very much been a man under pressure, with some Real supporters calling for the ex-Liverpool boss to leave the Santiago Bernabeu.
While rumours swirled around the club that star player Cristiano Ronaldo was unhappy with Benitez's approach to managing the team, defender Pepe has since claimed that the squad are very much behind their coach, and president Florentino Perez.
Nevertheless, Madrid have won only four of their last eight in La Liga and now trail leaders Barca by six points.
Los Merengues have at least remained unbeaten in the Champions League, and will qualify in first place in their group if they avoid defeat to Malmo next week.
Real also have the second most potent attack in the Primera Division, even though striker Karim Benzema has struggled for form since becoming embroiled in blackmail allegations concerning France teammate Mathieu Valbuena.
Recent form (all competitions): WWWLLW
Benitez is expected to ring the changes with the league game against Getafe to come, and Kiko Casilla is likely to start in goal, having featured regularly in cup competitions this season.
Alvaro Arbeloa could also start for Los Merengues, with Gareth Bale and Ronaldo possibly on the bench or even left out altogether, although with injuries blighting the first-team squad at the moment, the former Premier League stars could yet feature.
However, the game may offer the chance for Benzema to make his first start since the 4-0 drubbing at the hands of Barca.
Cadiz possible starting lineup:
Cifuentes, Juanjo, Servando, Aridane, Andres, Quintana, Abel, Hugo, Machado, Pla, Guiza
Real Madrid possible starting lineup:
Casilla, Pepe, Nacho, Danilo, Kroos, Rodriguez, Arbeloa, Kovacic, Modric, Benzema, Lazo
Head To Head
Cadiz have only met Real Madrid twice at senior level, with both encounters coming during the 2005-06 season, and both ending in defeat.
The first meeting in August 2005 saw Brazilian international Ronaldo open the scoring and, despite an equaliser from Matias Pavoni, Los Blancos snatched a late victory thanks to Raul's 84th-minute winner.
Real were stunned by Alexander Medina's opener in the return fixture in January, but goals from Roberto Carlos, David Beckham and a young Robinho saw Juan Ramon Lopez Caro's star-studded team take three points.
We say: Cadiz 0-3 Real Madrid
Although Los Merengues are expected to field several changes and have conceded 10 goals in their last four games in all competitions, most observers would still expect Real to leave Andalusia with a comfortable victory.