[5] Lozano began his career with Pachuca, winning the 2016 Clausura and the 2016–17 CONCACAF Champions League, playing in 152 games and scoring 44 goals for the team.

In June 2017, he signed for Dutch side PSV Eindhoven and won the Eredivisie in his first season in the Netherlands, also finishing as the team's top scorer.

[8] 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 Estadio Azteca.

[19] On 13 September, during the 2016–17 CONCACAF Champions League group stage, he scored four goals in their 11–0 defeat of Police United, helping Pachuca set the record for the biggest win in the history of the competition.

[24] In April, during the second leg of the CONCACAF Champions League semifinals against FC Dallas, Lozano scored twice within the last 10 minutes of the match to help lead Pachuca to a 3–1 win (4–3 on aggregate) to qualify to the finals.

[25] The following month, Pachuca won the CONCACAF Champions League by defeating fellow Mexican club Tigres UANL,[26] with Lozano winning the Golden Boot as the competition's top scorer with 8 goals,[27] as well as the Best Young Player Award.

[29] 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.

[34] 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.

[42] 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.

[44] Three days later, he made his UEFA Champions League group stage debut against Barcelona, playing all ninety minutes in PSV's 4–0 defeat.

[48][49] Four days later, he scored his first goal in the Champions League group stage as PSV drew 2–2 with Tottenham Hotspur, also managing to send Hugo Lloris off with a red card due to an outside-of-the-box infraction.

[54] 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.

[6] 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.

[57] Following Carlo Ancelotti's sacking for mediocre results, Gennaro Gattuso was named as the new manager, with Lozano initially receiving little to no playing time.

[60] Two days later, he appeared as an unused substitute in Napoli's Coppa Italia victory against Juventus, defeating them 4–2 in a penalty shoot-out following a scoreless draw, becoming the first Mexican to win a title with an Italian club.

[67] On 26 November, he scored his first Europa League goal in a group stage match against Croatian side Rijeka, sealing a 2–0 home victory.

[75] On 9 December, during Napoli's final Europa League group stage match against Leicester City, Lozano suffered a head injury after colliding with Wilfred Ndidi's knee in the 40th minute, being stretchered off the field.

[78] On 13 January, fully recovered from COVID-19, Lozano made his return as a 63rd-minute substitute in the Coppa Italia round of 16 match against Fiorentina, only to be sent off after twenty minutes following a late challenge on Nicolás González.

[83] On 29 October, he scored his first hat-trick at the club in a 5–2 victory over Ajax, to be the first player to achieve this feat for PSV against their rivals since Mark van Bommel in 2005.

Mexico went on to win the tournament, defeating Panama in a penalty shoot-out 4–2 following a 1–1 draw thus earning entry to the 2015 FIFA U-20 World Cup in New Zealand.

[90] 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.

[98] 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.

[101] 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.

[102] 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.

[108] On 1 September 2017, Lozano scored the only goal in the 2018 FIFA World Cup qualifying match against Panama, thus booking Mexico's qualification to the tournament.

[116] Lozano was included in coach Gerardo Martino's preliminary squad for the 2019 CONCACAF Gold Cup, however he was subsequently ruled out of the tournament after having not fully recovered from a knee injury suffered while playing with PSV.

[119] "When you look at his playing style, without wanting to compare, you know, Lozano has what Messi also has – a centre of gravity low to the ground, the ball is usually quickly under control, very explosive and agile."

[...] [He] is equally adept at creating chances as well as scoring them, with a strong left-foot he's able to deliver crosses after taking the ball down the line, although he elects to cut inside more often than choosing to go outside the opposition full-back.

[129] His diminutive stature and agile playing style has been cited as the reason for being the victim of various fouls, at one point becoming the most-fouled-on player in various seasons of the Liga MX.