Lozano joined Pachuca in 2009 as part of its youth team. On 8 February 2014, Lozano made his Liga MX debut against Club América, in which he scored five minutes after his substitution in the 1–0 win at the Estadio Azteca. In his debut tournament with the first team – the Clausura 2014 – Lozano finished runner-up with Pachuca, even scoring the third goal in the 3–2 first leg final win over León.

On 30 August 2014, Lozano scored his first brace against León, winning 2–1. On 13 September 2014, he would score Pachuca’s only goal in a 1–1 draw against Tijuana.

Lozano married his girlfriend Ana Obregon in 2014, whom he met while playing for Pachuca. The pair have two children; a daughter born in 2014, and a son born in 2017.

On 19 September 2015, Lozano scored an equalizer seven minutes after Dorados scored first in a league match where Pachuca went on to win 2–1. On 27 February 2016, Lozano scored the first and only goal of the encounter on the first minute of the match against Toluca, with the win placing them first place on the general table. On 19 March, Lozano scored his first hat-trick in Pachuca’s 6–0 defeat of Veracruz. Lozano contributed two goals during the semifinal legs of the 2016 Clausura championship against León, giving his team an aggregate score of 3–2. Pachuca won the league title after they defeated Monterrey 2–1 on aggregate in the finals of the Clausura 2016 tournament. Lozano was included in the Best XI of the Clausura 2016 tournament.

On 8 May 2015, Lozano was called up by Sergio Almaguer to participate in the CONCACAF U-20 Championship. In the first group stage match against Cuba, he scored a brace and added four assists in Mexico’s 9–1 win, placing them first in their group. He went on to score three more goals and notched another assist in the tournament. Mexico went on to win the tournament, thus earning entry to the 2015 FIFA U-20 World Cup in New Zealand. Finishing with five goals, he was proclaimed the Golden Boot winner along with United States midfielder Romain Gall; Lozano was also named in the tournament’s Best XI. Lozano was then called up to participate in the U-20 World Cup, where he would appear in all three group stage matches. Mexico would finish last in the group.

On 18 September 2015, Lozano was selected by coach Raúl Gutierrez to play in the CONCACAF Olympic Qualifying Championship. He scored Mexico’s second goal in the 2–0 semi-final win over Canada. Mexico ultimately won the tournament after defeating Honduras 2–0 in the final, with Lozano being awarded the tournament’s Golden Ball as well as being included in the tournament’s Best XI.

In 2015, Lozano was named by Don Balón as one of the best players in the world born after 1994. Upon his arrival to PSV Eindhoven, he was named among the top Eredevisie young players to watch for the 2017–18 season. FIFA named Lozano in their list of young stars of 2017. Multiple sources considered him a breakout star of the 2018 FIFA World Cup. He was listed on Goal.com’s 2018 Goal 50 list of the fifty best players in the world. He was also included in The Guardian’s 2018 list of The 100 best footballers in the world. FourFourTwo included Lozano in their 2018 list of the 100 Best Football Players in the World.

On 16 July 2016, Lozano scored a brace and contributed an assist in the first league match against León, winning 5–1. On 13 September, during the 2016–17 CONCACAF Champions League group stage, he scored four goals against Police United, helping Pachuca set the record for the biggest win in the history of the competition with an 11–0 victory. On 15 October, Lozano would contribute an assist and score in Pachuca’s 3–0 victory over Santos Laguna. Lozano finished the Apertura 2016 tournament as the highest-scoring Mexican player with seven goals. He would go on to be listed on the Best XI of the Apertura 2016.

On 7 July 2016, Lozano was named in the 18-man squad that would participate in that year’s Summer Olympics in Rio de Janeiro, Brazil. In Mexico’s third group stage match against South Korea on 10 August, Lozano was sent off in stoppage time after shoving a Korean player. Mexico lost the match 1–0, finishing third in their group and were thus eliminated from the competition.

Lozano received his first call-up to the senior national team in February 2016 under coach Juan Carlos Osorio. On 10 February, Lozano earned his first cap as a starter in the friendly against Senegal, assisting fellow Pachuca teammate Rodolfo Pizarro in the second goal as Mexico won the match 2–0. The following month, Lozano scored his first international goal in the 39th minute of the 2018 FIFA World Cup qualifying third round match against Canada, which Mexico won 3–0. He was included in Mexico’s 23-man squad to participate at the Copa América Centenario, he appeared in all matches of the tournament, culminating in a quarter-final exit.

On 19 June 2017, Dutch club PSV Eindhoven announced the signing of Lozano on a six-year contract.

Lozano made his competitive debut for PSV in the Europa League qualifiers against Croatian side Osijek, playing in both legs as they failed to make the group stage as a result of a 2–0 aggregate score. On 12 August, Lozano scored on his Eredivisie debut with PSV against AZ Alkmaar. He started and played 84 minutes in his team’s 3–2 victory, receiving a standing ovation from the home fans as he was subbed off. A week later, he scored once again and provided an assist in PSV’s 4–0 win over NAC Breda. The following week, Lozano scored again in PSV’s 2–0 victory against Roda JC; he became the first player to score in his first three games with PSV, and he was later named Eredivisie Player of the Month for the month of August. On 10 September 2017, Lozano received his first red card for PSV in a 2–0 defeat against SC Heerenveen.

On 8 June 2017, Lozano was named in Mexico’s 23-man squad for the FIFA Confederations Cup in Russia. In their final group stage match against the hosts, Lozano scored the second goal in a 2–1 win after chasing a long clearance from Héctor Herrera and beating goalkeeper Igor Akinfeev to the ball towards the edge of the box, allowing Lozano to nip in and head it into the open net. His performance led him to be named man of the match.

On 1 September 2017, during a 2018 FIFA World Cup qualifying match against Panama, Lozano scored the game’s only goal, thus booking Mexico’s qualification to the tournament. On 10 November, he scored his first brace with the national team in a 3–3 draw against Belgium, scoring off a lobbed ball from Héctor Herrera on the 56th minute and scoring off a volley following a rebound from his first shot off of goalkeeper Thibaut Courtois two minutes later.

On 17 February 2018, Lozano received his second red card of the season, again during a league match against Heerenveen, for making contact with defender Lucas Woudenberg’s face. He was handed a three-match suspension which was ultimately upheld by the KNVB disciplinary committee after a failed appeal by PSV. Lozano made his return on 18 March, scoring the second goal in PSV’s 3–0 victory over VVV Venlo, his 14th goal of the season.

Lozano appeared as a second-half substitute in PSV’s first match of the 2018–19 season, against Feyenoord in the 2018 Johan Cruyff Shield. With the match tied 0–0 at full time and going into penalties, Lozano successfully converted one but ended on the losing side of a 6–5 loss. On 11 August, Lozano scored in PSV’s 2018–19 Eredivisie opener against FC Utrecht, scoring the third goal in their 4–0 victory. He scored again the following week in a 2–1 victory over Fortuna Sittard. Three days later, Lozano made his UEFA Champions League debut against BATE; he scored PSV’s second goal in their 3–2 victory in the first-leg of the playoff qualification round.

On 4 June 2018, Lozano was named in Mexico’s 23-man squad for the World Cup. On 17 June, he scored the lone goal, thanks to an assist by Javier Hernández, in the opening group match win over defending champions Germany. He was named FIFA Man of the Match for his performance. On 23 June, in Mexico’s second match against South Korea, Lozano provided the assist to Javier Hernández in scoring the second goal in their 2–1 win. Lozano started in all four matches as they were eliminated by Brazil in the round-of-16.

On 25 April 2019, during a match against Willem II, Lozano was stretchered off the field after a challenge from Freek Heerkens. It was initially thought that the player may have suffered cruciate ligament damage and was facing a lengthy spell on the sidelines, however that was eventually ruled out. The club later released a statement stating Lozano would miss the remainder of the season.

On 23 August 2019, Lozano officially joined Italian club Napoli. He reportedly signed a five-year contract with a transfer fee of US$46.5 million (€42 million), making Lozano Napoli’s most expensive signing at the time, as well as the highest transfer fee paid for a Mexican player, and the largest fee received by PSV Eindhoven for a player. Eight days later, Lozano made his Serie A debut as a second-half substitute against Juventus in Turin, scoring his side’s second goal in a 4–3 defeat.

Following Carlo Ancelotti’s sacking for mediocre results, Gennaro Gattuso was named as the new manager, with Lozano receiving little to no playing time. In June 2020, he won the Coppa Italia against Juventus, defeating them 4–2 in a penalty shoot-out following a scoreless draw, becoming the first Mexican to win an Italian title. During the final fixtures of his first season with Napoli, Lozano received more playing time, finishing with 26 league matches with 4 league goals under his name.