New Sevilla coach Diego Alonso faces a stern test in his first game at the helm and in experienced veteran centre-back Ramos, he has a player who can offer plenty of insight into Carlo Ancelotti's Madrid side.
Ramos controversially left Seville for the Spanish capital at the age of 19, which some fans have never forgotten, even though the majority welcomed him back with open arms this summer.
"We believe that the mere proposal of this signing was already a lack of respect for the values that have made us great... and for the thousands of Sevilla fans who have suffered the scorn of this player in the past," wrote Sevilla ultras group Biris Norte in an open letter.
In the years after his departure, Ramos was keen to goad his former side, while he was roundly booed on visits to face Seville.
However, the defender said he could "die happy" after playing for his boyhood club again, and has impressed since returning even though the team was struggling under Jose Luis Mendilibar.
"I had a few doubts at first but the reception I had on my arrival, I will take to the grave ... now I can die happy," said Ramos after his first match back at the Sanchez-Pizjuan, a win over Las Palmas.
One sour note was his own goal against old rivals Barcelona, handing the champions a 1-0 win at the Catalan club's temporary Olympic Stadium home at the end of September.
Ramos will hope his first clash with Real Madrid goes better, although it promises to be an emotional affair for him.
He left Madrid for French side Paris Saint-Germain in 2021 but was injured when the sides met in the Champions League in March 2022.
The last time Ramos faced Madrid was for Sevilla in May 2005, and he scored in a 2-2 draw, hammering home a long-range drive after a free-kick was laid off to him.
Ramos has never lost a game against Real Madrid - the other time he faced them Sevilla won 1-0 at the Santiago Bernabeu.
Madrid will want to keep, or even extend, their three-point advantage over Barcelona ahead of the Clasico on October 28th.
Barcelona host former coach Ernesto Valverde's Athletic Bilbao on Sunday in another reunion, with the Catalans currently third.
Girona, second, welcome bottom-of-the-table Almeria on Sunday and will be confident of staying ahead of their more illustrious Catalan neighbours.
Sevilla are 14th, with only two wins in their first eight games and only two points clear of the relegation zone.
The Madrid clash is only the start of a tough run of games for Alonso and his side, with Arsenal visiting on Tuesday in the Champions League, and a derby clash against Real Betis in La Liga on the horizon.
Player to watch: Ferran Torres (Barcelona)
The Spanish Barcelona forward has become an important figure for Xavi in the absence of Robert Lewandowski and Raphinha. Torres has four goals across all competitions this season in 10 appearances and is set to lead the line against Athletic Bilbao on Sunday.
Key stats
11 - Atletico's Alvaro Morata and Real Madrid's Jude Bellingham have scored more goals than any other player for their clubs and countries combined this season, level along with Man City's Erling Haaland
21 - Real Betis playmaker Isco has made the most passes into the area in La Liga
49 - It's safety first for Celta Vigo's Carl Starfelt, who has the most clearances in the league
Fixtures (all times BST)
Friday
Osasuna v Granada (8pm)
Saturday
Real Sociedad v Real Mallorca (1pm), Getafe v Real Betis (3.15pm), Sevilla v Real Madrid (5.30pm), Celta Vigo v Atletico Madrid (8pm)
Sunday
Las Palmas v Rayo Vallecano (1pm), Girona v Almeria (3.15pm), Villarreal v Alaves (5.30pm), Barcelona v Athletic Bilbao (8pm)
Monday
Valencia v Cadiz (8pm)