Pérez joined the Union of the Democratic Centre party in 1979, serving among others on the Madrid city council.

In 1986, Pérez ran in the Spanish general elections as candidate for the Partido Reformista Democrático (Democratic Reform Party).

In 1993, he was named vice President of OCP Construcciones. After the fusion of OCP with Gines y Navarro into Actividades de Construcción y Servicios, S.A. (ACS) in 1997, he became President of the new company.

Florentino Pérez first ran for the presidency of real Madrid in the 19 February 1995 election. He campaigned on the poor financial situation of the club and the alleged extensive mismanagement by the board, but lost to the incumbent Ramón Mendoza by 699 votes.

His second attempt was more successful; he took over as President in 2000, beating the current chairman at that time, Lorenzo Sanz. Sanz assumed that the recently won European Cups in 1998 and 2000 would give him enough credit to win the elections, but Pérez's campaign, once again highlighting the financial problems of the club and claims of mismanagement by the previous boards, proved otherwise. Pérez's promise to bring in Luís Figo from arch-rivals Barcelona also played a decisive role in the elections. Pérez was reelected in 2004 with 94.2% of the total votes.

Figo also marked the start of Pérez's policy to bring one of the best football players in the world to real Madrid each season. The strategy was initially known as that of Zidanes y Pavones - in which superstars would play alongside the Canteranos, but the players were soon popularly referred to as Galácticos. In 2001, Zinedine Zidane was signed from Juventus for a then-world record transfer fee of €77.5 million. He was followed by Ronaldo in 2002, David Beckham in 2003, Michael Owen in 2004 and Robinho for a short while in 2005. Initially, Pérez's policy worked to great success, as each new Galáctico had the squad built around them, and the team had a good balance between attack and defence. In his first years in office, real Madrid won two Spanish championships and its record ninth European Cup.

Several years after leaving real, McManaman and Morientes stated that Makélélé was the most important and least appreciated midfielder, the latter saying, "The loss of Makélélé was the beginning of the end for Los Galácticos... You can see that it was also the beginning of a new dawn for Chelsea." From the 2003–04 season onward, with the absence of del Bosque and Makélélé, real Madrid failed to win a trophy.

Though Pérez's policy resulted in increased financial success based on the exploitation of the club's high marketing potential around the world, especially in Asia, it came under increasing criticism for being focused too much on marketing the real Madrid brand and not enough on the football. He announced his resignation on 27 February 2006, acknowledging that the team and the club as a whole needed a new direction.

On 5 August 2009, real Madrid confirmed the signing of Xabi Alonso from Liverpool for £30 million; Alonso became the second Liverpool player to join real Madrid in the same transfer window after full-back Álvaro Arbeloa's £5 million switch to the Santiago Bernabéu in July.

During the next three years, Pérez brought a lot of new faces to the team, including the German wonderkid Mesut Özil, and Ángel Di María, who both attracted attention from Europe's elite football clubs during the 2010 World Cup in South Africa. This squad enjoyed its share of domestic success in 2011 and 2012, with the club bringing home a Copa del Rey title and the Spanish League title. However, the club's lack of success in European competition and a disappointing 2012–13 season encouraged Mourinho to depart for his former club Chelsea.

On 2 June 2013, Pérez was awarded a fourth term as the real Madrid President, bringing in Carlo Ancelotti to replace Mourinho. Mesut Özil and Gonzalo Higuaín were sold to Arsenal and Napoli, respectively, at the start of the season to secure spots for Luka Modrić and Karim Benzema in the first team. Pérez also brought in Welsh footballer and PFA Player of the Year Gareth Bale, purchased from Tottenham Hotspur for a fee reported to be in the £86 million range, yet again breaking the world record. Two promising Spanish talents, playmaker Isco and holding midfielder Asier Illarramendi, were also secured by Pérez prior to the start of the season. The following season proved to be a resounding success, as real Madrid won the Copa del Rey and its tenth Champions League title.

During the 2014 summer transfer window, Pérez brought in 2014 FIFA World Cup stars James Rodríguez, Toni Kroos, and Keylor Navas to real Madrid for a combined cost of £95 million, as well as Javier Hernández on a loan deal from Manchester United. As a result of the mounting competition for starting spots and wage disputes, Ángel Di María left the club for Manchester United for a British record transfer fee of £60 million. Xabi Alonso also left during this transfer window to join Bayern Munich. In January 2015, Pérez again showed his muscle in the transfer market when real Madrid signed the 14-year-old Norwegian Martin Ødegaard in competition with many of the big clubs in Europe, including Bayern, Barcelona and Arsenal.

After Iker Casillas' move to Porto in July 2015, Casillas' agent, Santos Márquez, criticized Pérez, "He doesn't like black players, but is not a racist," and that is why players like Claude Makélélé and Samuel Eto'o weren't paid as much as other players. Márquez also expressed that he expects Pérez to leave real Madrid after Casillas' transfer.