Product of Defensores de Cambaceres lower divisions, Pratto joined Argentine club Boca Juniors in 2006, after a recommendation by Martín Palermo. Once in the La Boca-based team, he was sent to the team’s fifth division, where he scored more than 20 goals and formed an attacking partnership with Óscar Trejo.

In June 2007, he was loaned to Tigre, but mostly played for the reserve team in their first season. Leandro Lázzaro’s departure to Estudiantes, however, allowed Pratto to break into the starting eleven and challenge the possibility of being the team’s first choice striker. Following Lázzaro’s absence, Lucas played ten 2008 Clausura games and scored one goal against San Martín de San Juan, which was his side’s winning goal in a 2–1 home win at José Dellagiovanna.

On 2 August 2008, Pratto joined Norway’s Lyn Fotball on a free loan from Boca, after being recommended by the scout Terje Liverød who helped with the negotiations. On 15 August, Lucas made a goalscoring debut during a 3–1 defeat against Molde FK in a Tippeligaen game as a 71st-minute substitute. Between 2008 and 2009 Pratto made 21 league appearances and scored four goals for Lyn. He then returned to Argentina in mid-2009 to join Boca’s first-team squad, then coached by Alfio Basile.

On 29 June 2010 Pratto joined Chile’s Universidad Católica on loan from Boca, this time as part of Gary Medel’s contract extension negotiation. In the Chilean club, Pratto scored in his debut against Everton in a 1–1 league draw at Viña del Mar. At first, Lucas was heavily criticized for his bad shape at the Las Condes-based team, but key goals in the end of the season against Universidad de Chile and Cobreloa helped Católica achieve their 10th Campeonato Nacional title. He had an impressive season start in 2011 when he scored six Copa Libertadores goals (including a brace against Grêmio, in a historic 2–1 triumph at Brazil) and six league goals, which allowed him be sold by Boca to Italian Serie A side Genoa for a US$2,4 million fee.

Pratto was raised by his mother Daniela, helped by his older brother Leandro. Aside from him, Lucas has three other siblings from his father’s other family. Pratto has one daughter, Pia, born in 2010, and has tattoos portraying her and his mother. Lucas has an interest on rock and roll, being a fan of AC/DC, Foo Fighters, Kiss and Argentine band La Renga, of whom he also has a tattoo. He is also an avid fan of The Simpsons, has tattoos of both Homer and Bart, and an English bulldog named Santa’s Little Helper. Pratto has stated that he is a Boca Juniors supporter. He holds an Italian passport.

Pratto joined the Genovese club on 30 June 2011, being described months before by the club’s president Enrico Preziosi as the team’s new Diego Milito. He officially debuted as a starter during Genoa’s first 2011–12 Coppa Italia game against Nocerina in a 4–3 home win, in which he scored his side’s second goal after an assist by Kévin Constant. His Serie A debut was on 11 September in a 2–2 draw with Atalanta for the league’s first matchday, and his first goal came on 18 December in a 2–1 victory over Bologna, the match-winner at the 85th minute. His second goal for Coppa Italia was on 24 November against Bari in a 3–2 victory, where once again he scored the match’s winning goal, now after an impressive header in the 115th minute during extra-time. Pratto made an attacking partnership with Rodrigo Palacio, but coach Alberto Malesani, by whom he was selected for the first squad, was fired in December 2011. Since that time Lucas failed to play the rest of season, being relegated to the bench by the team’s next coaches (Pasquale Marino, the same Malesani and Luigi De Canio).

On 7 February 2012 it was reported that Pratto had joined Vélez Sarsfield in a season-long loan deal, with the option to be fully signed by the Argentine club. After a decent first season with the Liniers side, in which he played 20 times and scored 4 goals, Lucas became a starter during Vélez’s 2012 Torneo Inicial championship-winning campaign. Pratto made a partnership with Facundo Ferreyra, and played a key role appearing in all 19 games and scoring seven goals.

In January 2013 it was reported that Vélez had come to an agreement with Genoa for the definitive purchase of the player on a three-year contract. On 29 June 2013, Lucas scored the match winner in the Superfinal, the match that concluded the 2012–13 Primera División season, as Vélez defeated Newell’s 1–0 and were crowned Super Champions. At the end of the year Pratto was selected as Vélez’s best player of the season.

On 16 December 2014, Lucas Pratto joined Brazilian club Atlético Mineiro on a four-year contract. Pratto made his unofficial debut and scored his first goal for Atlético in a pre-season friendly against Shakhtar Donetsk, which his new team won 4–2. Pratto also scored in his first official match for the club, against Tupi, for the 2015 Campeonato Mineiro, as well as in his debut in Copa Libertadores for Atlético, scoring the winner in a 1–0 away win against Independiente Santa Fé.

In the second leg of the Campeonato Mineiro semifinals against fierce rivals Cruzeiro, Pratto managed to score a brace with two assists by Guilherme, one of the goals an impressive volley, and helped his team make a 2–1 comeback after trailing in half-time. Atlético were eventually crowned champions of the competition, with Pratto finishing with six goals and being selected for the team of the tournament and as its best player. In July 2015, Pratto became Atlético’s highest-ever foreign goalscorer and scored his first-ever hat-trick, with all three goals coming in the first half of a 3–1 home win against São Paulo. He still holds this record as the club’s highest-ever foreign goalscorer, with 42 goals.

Pratto received his first international call-up for Argentina on 12 August 2016, for 2018 FIFA World Cup qualification matches against Uruguay and Venezuela. He started for the national team for the first time in the match against Uruguay on 1 September 2016, and scored his first goal against Venezuela on 7 September. Pratto scored his second international goal helping Argentina to a 3–0 win over Colombia in November 2016.

On 10 February 2017, Pratto signed a four-year contract with Brazilian club São Paulo FC. The transfer totalled around €12 million, with the São Paulo-based club paying approximately €6 million for 50 per cent of the player’s rights. According to Carlos Augusto de Barros e Silva, São Paulo’s president, the club would acquire up to 95% of the rights in the future. Atlético Mineiro president Daniel Nepomuceno stated that payment for the remaining shares would occur within three years.

On 9 July 2017, Pratto lost a penalty kick in a 3–2 loss of São Paulo FC against rivals Santos FC. At the end of this match, he was seven consecutive games without scoring any goal.

On 8 January 2018, São Paulo confirmed the selling of Pratto to River Plate for €11.5 million, becoming River’s highest ever transfer acquisition.