In 2007, Juan Jesus joined the youth team of Sport Club Internacional. He made his debut on the first team in 2010, winning the 2010 Copa Libertadores, and in December 2011, the club sold him for about R$9.26 million (reported €3.8million fee); 65% of the economic rights of Juan went to his agent, Giuliano Bertolucci and 35% to third-party owner DIS Esporte. The owners of the registration rights of Juan, used a Brazilian club Coimbra Esporte Clube as middleman club.

After having played in the under-18 and under-19 national teams, in early 2010, Juan Jesus was selected to the under-20 team by its manager, Ney Franco. In January 2011, he took part in the team’s triumph at the 2011 South American U-20 Championship in Peru, playing all eight matches of the competition. In the same year, he participated in the FIFA U-20 World Cup, where Brazil reached the final against Portugal. Juan played the entire match, helping his side to a 3–2 victory after extra time.

On 30 January 2012, Juan Jesus joined Serie A club Internazionale. Inter disclosed the fee was €4M, but extra bonus clause was also reported. He made his first Serie A appearance for Inter on 13 May 2012, in the 3–1 away loss against Lazio after coming on as a last-minute substitute for Diego Milito.

Juan Jesus made his Brazilian first team debut against Denmark on 26 May 2012, playing the full 90 minutes in a 1–3 away victory.

During the 2012–13 season, Juan Jesus emerged as part of Inter’s first choice starting XI, featuring alongside Andrea Ranocchia and Walter Samuel in a 3–5–2 system. He scored his first goal on 19 May 2013 in a 2–5 home defeat against Udinese, the last match of the domestic season. He ended the year with 44 appearances in all competitions, including 31 in Serie A with Inter, who finished the season in a disappointing ninth place and failed to qualify for either next season’s UEFA Champions League or UEFA Europa League.

On 12 July 2013, Juan Jesus took the number 5 shirt after the departure of long-time player Dejan Stanković. In August 2013, he captained Inter for the first time in a friendly match against Real Madrid in the United States, which ended in a 3–0 loss.

On 24 September 2013, Juan Jesus renewed his contract with Inter until 2018 with a reported wage of €1.2 million per year.

Juan Jesus made his 100th appearance for Inter on 4 February 2015 in a game against Napoli in the quarter-finals of the Coppa Italia, which the Nerazzurri lost 1–0 away at Stadio San Paolo thanks to a late winner by Gonzalo Higuaín.

On 14 July 2016, Juan Jesus join A.S. Roma on loan with a €2million in loan fees and a conditional obligation to purchase for an additional €8 million after a certain sport objectives. The obligation was activated in the mid of 2016–17 season; the club booked a loan fee of €1.153 million and an additional transfer fee €8.847 million in the financial report instead.