There is often a fierce rivalry between the two strongest teams in a national league, and this is particularly the case in La Liga, where the game between Real Madrid and Barcelona is known as "The Classic" (El Clásico). From the start of national competitions, the clubs were seen as representatives of two rival regions in Spain, Catalonia and Castile, as well as of the two cities. The rivalry reflects what many regard as the political and cultural tensions felt between Catalans and the Castilians, seen by one author as a re-enactment of the Spanish Civil War. Over the years, the record for Real Madrid and Barcelona is 96 victories for Madrid, 96 victories for Barcelona, and 51 draws.

During the dictatorships of Miguel Primo de Rivera (1923–1930) and especially of Francisco Franco (1939–1975), all regional cultures were suppressed. All of the languages spoken in Spanish territory, except Spanish (Castilian) itself, were officially banned. Symbolising the Catalan people's desire for freedom, Barcelona became "More than a club" ("Més que un club") for the Catalans. According to Manuel Vázquez Montalbán, the best way for the Catalans to demonstrate their identity was by joining Barcelona. It was less risky than joining a clandestine anti-Franco movement, and allowed them to express their dissidence. During Franco's rule, however, Barcelona was granted profit due to its good relationship with the dictator at management level, even giving two awards to him.

On the other hand, Real Madrid was widely seen as the embodiment of the sovereign oppressive centralism and the fascist regime at management level and beyond: Santiago Bernabéu, the former club president for whom Real Madrid's stadium is named, fought on the Nationalist side during the Spanish Civil War. During the Spanish Civil War, however, members of both clubs such as Josep Sunyol and Rafael Sánchez Guerra suffered at the hands of Franco supporters.

During the 1950s, the rivalry was exacerbated further when there was a controversy surrounding the transfer of Alfredo Di Stéfano, who eventually played for Real Madrid and was key to their subsequent success. The 1960s saw the rivalry reach the European stage when they met twice in a controversial knock-out round of the European Cup, with Madrid receiving unfavourable treatment from the referee. In 2002, the European encounter between the clubs was dubbed the "Match of The Century" by Spanish media, and Madrid's win was watched by more than 500 million people. An intense fixture which is marked by its indiscipline in addition to memorable goal celebrations from both teams – often involving mocking the opposition. Notable examples of this occurred in October 1999 when Raúl silenced the hostile crowd of 100,000 Barcelona fans when he scored and then celebrated his goal by putting a finger to his lips as though to tell them to be quiet.

The club's nearest neighbour is Atlético Madrid, a rivalry being shared between fans of both football teams. Although Atlético was founded by three Basque students in 1903, it was joined in 1904 by dissident members of Madrid FC. Tensions escalated further after Atlético were merged with the football team of the Spanish airforce (and thus renamed Atlético Aviación), and in the 1940s, Atlético was perceived as the preferred team of Franco's regime before he revelled in Real's European success in the 1950s. Furthermore, Real supporters initially came from the middle and upper classes while the Atlético supporters were drawn from the working class. Today, however, these distinctions are largely blurred. They met for the first time on 21 February 1929 in matchday three of the first League Championship at the former Chamartín. It was the first official derby of the new tournament, and Real won 2–1.

The rivalry first gained international attention in 1959 during the European Cup when the two clubs met in the semi-final. Real won the first leg 2–1 at the Bernabéu while Atlético won 1–0 at the Metropolitano. The tie went to a replay, which Real won 2–1. Atlético, however, gained some revenge when, led by former Real Madrid coach José Villalonga, it defeated its city rivals in two successive Copa del Generalísimo finals in 1960 and 1961.

A further minor rivalry exists between Real Madrid and Athletic Bilbao. This is known as El Viejo Clásico (the old classic), so named as the two clubs were dominant in the first half of the 20th century, meeting in nine Copa del Rey finals including the first in 1903. Until 10 December 2011, this fixture was the most played in the history of Spanish football, when it was surpassed by El Clásico.

Athletic Bilbao, who operate a policy of only using local players, have long since ceased to be a competitive rival to clubs such as Real Madrid who scour the globe for the best talent; the Lions have collected no major trophies since 1984 and won only two of the 26 matches between the teams from 2005–06 to 2016–17. However, the matches remain keenly fought due to their historical and cultural significance, with some parallels to the political aspect of the Barcelona/Catalonia rivalry as Athletic are the largest club in the Basque region.

Real Madrid and Germany's Bayern Munich are two of the most successful clubs in the UEFA Champions League/European Cup competition, Real winning thirteen times and Bayern winning six times. Although they have never met in a final, Real Madrid versus Bayern is the match that has historically been played most often in the Champions League/European Cup with 26 matches (12 wins for Madrid, 11 wins for Bayern, with 3 draws), with several controversial incidents occurring due to the great importance of most of their meetings. Real Madrid supporters often refer to Bayern as the "Bestia negra" ("Black Beast").

During the 2010s, the two teams met in the 2011–12 Champions League semi-finals, which ended 3–3 on aggregate (Bayern won 3–1 on penalties after extra time, but lost the final at their own stadium), and then at the same stage in the 2013–14 edition with Real Madrid winning 5–0 on aggregate on their way to winning the competition. They were also drawn together in the 2016–17 quarter-finals; Real Madrid won 6–3 on aggregate and subsequently lifted the trophy. The following year, they met in the semi-finals, with Real Madrid again progressing 4–3. Until the 2018–19 season when they were twice defeated in Madrid by three-goal margins, Real's biggest loss at home in the Champions League had been at the hands of Bayern on 29 February 2000, 2–4.

Another match that is often played in the European Cup/Champions League is Real Madrid vs Juventus, the most decorated Italian club. They have played each other in 21 matches and have an almost perfectly balanced record (9 wins for Juventus, 10 wins for Real Madrid, 2 draws), as well as nearly the same goal difference (Madrid ahead 26 to 25).

Their first meeting was in the 1961–62 European Cup, which Real Madrid won 3–1 in a replay held in Paris. At the quarter-final stage in 1995–96, Juventus prevailed 2–1 and went on to lift the trophy. In the 1998 UEFA Champions League Final between the teams in Amsterdam, Real Madrid won 1–0. They met again in the 2002–03 UEFA Champions League semi-finals, when both clubs were in their respective 'golden eras'; Juventus won 4–3 on aggregate. By that time, star midfielder Zinedine Zidane, who played for the Bianconeri in the 1998 final, had moved from Turin to Madrid in a world record €77 million deal.

In the 2014–15 UEFA Champions League semi-finals, former Real Madrid player Álvaro Morata scored one goal in each leg to take Juventus to the final, winning 3–2 on aggregate. They faced off again in the 2017 UEFA Champions League Final in Cardiff, which Real Madrid won 4–1. Portuguese player Cristiano Ronaldo scored two goals in the match, and was named man of the match.