Guardado started playing professionally for Atlas FC, joining the team’s youth system at the age of seven and going on to appear in two full Primera División seasons. He made his league debut on 20 August 2005, in a 3–2 home win against C.F. Pachuca, and on 15 October, scored his first goal against Tigres UANL in a 2–1 away victory.

Guardado made his first appearance for Mexico in a friendly match against Hungary on 14 December 2005, four months after his first-team debut with Atlas. He was then called up to represent his country at the 2006 FIFA World Cup in Germany, where he appeared in the round of 16 1–2 loss to Argentina, starting as a shifting attacking midfielder/wing-back alongside Ramón Morales but was replaced by Gonzalo Pineda after picking up an injury in the second half; after the departure of manager Ricardo La Volpe, his replacement Hugo Sánchez kept the player in his squad.

Guardado married fellow Guadalajara native Briana Morales in December 2006. Five years later, they divorced.

In the summer of 2006, press speculation linked Guardado to several Serie A teams as well as Real Madrid, but Deportivo de La Coruña moved quickly and made an offer of €7 million for 75% of his rights. Atlas accepted the offer and the transfer was finalized on 7 July 2007, making him the most expensive ever Mexican player at the time. Atlas retained a 25% sell-on-fee as long as it held the remaining 25% of his rights.

Guardado was officially introduced on 24 July 2007, with the Spanish team giving him the number 18 shirt. He made his La Liga debut on 26 August in a 0–3 home loss against UD Almería, and finished his first season with 26 games and five goals as Depor finished in ninth position, eventually qualifying to the UEFA Intertoto Cup – and the subsequent UEFA Cup, where he scored in a 3–0 group stage home win over Feyenoord.

Guardado’s first game under the new manager was an exhibition game against the United States, where he came on as a bench in a 0–2 defeat. On 28 February 2007, in a friendly with Venezuela, he scored his first international goal (3–1 win).

In May 2011, Guardado was called up by José Manuel de la Torre for the 2011 Gold Cup. He scored his first brace with the national team during that tournament, in a 4–1 win over Costa Rica on 12 June. He found the net again in the final in a 4–2 victory over the United States, as Mexico retained the trophy.

Guardado only managed to appear in 20 matches in 2010–11, and the Galicians were relegated to Segunda División after 20 years. On 27 March 2012 he confirmed that 2011–12 would be his last season with the club, and he scored a career-best 11 goals as his team returned to the top level as champions. Halfway through the season, he was voted by their fans as best player, and was also named the competition’s best attacking midfielder; additionally, he eventually surpassed Juan Carlos Valerón as the highest provider of assists.

On 28 May 2012, Guardado signed a four-year contract with Valencia CF. He made his debut on 19 August, playing 66 minutes in a 1–1 away draw against Real Madrid. His maiden appearance in the UEFA Champions League took place on 12 September, in a 1–2 group stage loss at eventual winners FC Bayern Munich; during his first season he featured regularly at left back, mainly due to the serious injury of Jérémy Mathieu.

Guardado scored his first goal for the Che on 12 May 2013, contributing to a 4–0 rout at Rayo Vallecano, and he featured mostly in the backline in the following months. On 30 January 2014, Bundesliga club Bayer 04 Leverkusen announced that they had signed him on loan for the rest of the season, with an option to buy afterwards. He made his debut on 2 February in a 0–1 loss against 1. FC Kaiserslautern for the DFB-Pokal, playing as a left wing-back.

For 2014–15, still owned by Valencia, Guardado joined PSV Eindhoven. He made his Eredivisie debut on 31 August 2014 against Vitesse Arnhem at Philips Stadion. He managed to wear the captain’s armband within his first months, won the Player of the Month award for November, and on 7 March of the following year he scored his first goal for his new club, contributing to a 3–0 away victory over Go Ahead Eagles.

On 5 March 2014, Guardado made his 100th appearance for Mexico in a friendly with Nigeria. Selected by Miguel Herrera for the 2014 World Cup in Brazil, he started all the games as a left midfielder, and scored in the last group phase fixture against Croatia, a 3–1 win; following the end of the tournament, the manager declared the player would captain the following September friendlies with Chile and Bolivia, captaining for instances when actual captain Rafael Márquez was absent.

In 2014, under Miguel Herrera’s improvisation, Guardado began to play as a defensive midfielder for the national team. At PSV, manager Phillip Cocu facilitated his positional change as injuries hampered his speed, as the latter began to operate as a central midfielder with box-to-box and deep-lying playmaker qualities; he later took on more defensive duties.

On 15 March 2015, prior to the match against FC Groningen and amidst rumours of a transfer to AFC Ajax, PSV fans displayed a Mexican flag tifo and a banner in Spanish which read “Andrés Guardado, our Golden Mexican Eagle. He has to stay in PSV Eindhoven. Our house is your house, Andrés”. On 27 March, PSV announced that they had reached a deal with Valencia over a permanent transfer, for an undisclosed fee and three years.

On 18 April 2015, with three matches to spare, the team won the league championship after a 4–1 win over SC Heerenveen, with Guardado playing the full 90 minutes. At the end of his first season, his impressive performances led him to be named the player of the year by Dutch magazines Algemeen Dagblad and Voetbal International; his displays also led to his inclusion in that year’s FIFA Ballon d’Or longlist.

On 31 July 2016, Guardado was in the starting eleven against Feyenoord, who were defeated 1–0 in the Johan Cruyff Shield. On 14 May 2017, he made his 100th appearance for the club in a 4–1 victory over PEC Zwolle.

Picked for the Copa América Centenario squad by Juan Carlos Osorio, Guardado provided a cross in the opening fixture against Uruguay that led to an own goal but was also sent off for two bookable offences, winning 3–1 at University of Phoenix Stadium on 5 June 2016. He took part in a further two games, in a quarter-final exit.

Despite rumors linking him to a possible move to Atlanta United and Los Angeles FC of the Major League Soccer, it was announced on 27 July 2017 that Spanish club Real Betis had signed Guardado for a reported €2.3 million on a three-year deal. The following month he was named their co-captain, and on 20 August he made his competitive debut, playing all 90 minutes in a 2–0 loss to FC Barcelona. He scored his first goal on 25 November, in a 2–2 home draw against Girona FC.

Guardado is an “honorary associate” of the Asociación Mexicana de Futbolistas (Mexican Footballers Association), created in October 2017. An association that its main goal is, according to him, to “create a dialogue with league, federation and club authorities” with the domestic footballers.

In December 2019, the 33-year-old Guardado renewed his contract until 2022. On 4 July 2020 he made his 100th official appearance for the Andalusians, captaining the side in their 1–1 league draw to RC Celta de Vigo and becoming the first Mexican to reach that mark for three different clubs in the process.

Guardado was called up by Gerardo Martino to participate in the 2019 Gold Cup. In the second group match against Canada, he replaced the injured Érick Gutiérrez at the 37th minute and scored twice, helping to a 3–1 win and being named Player of the match. He broke various CONCACAF-based records at the end of that stage, among them the most-capped Mexican player in the Gold Cup and the only from the country to score in four editions of the CONCACAF Gold Cup, eventually winning the competition and being included in the Best XI.