In 2004, Villas-Boas married Joana Maria Noronha de Ornelas Teixeira, with whom he now has two daughters, Benedita (born August 2009), Carolina (born October 2010) and a son, Frederico (born May 2015). He speaks English fluently, having been taught by his paternal grandmother Margaret Kendall, whose mother moved to Portugal from Cheadle, Greater Manchester, England, to start a wine business. Her brother Douglas Kendall served as a wing commander for the RAF during the Second World War.

At the start of the 2009–10 season, Villas-Boas left Mourinho’s team to pursue a career as a manager, and he soon found a job in the Primeira Liga with Académica de Coimbra, filling a vacancy created by Rogério Gonçalves’ resignation in October 2009. At the time of his appointment, Académica were at the bottom of the league and still without any wins, but their luck started to change as he introduced a new style, leading them to a safe 11th place, ten points clear of the relegation zone. In addition to that, Académica also reached the 2009–10 Portuguese League Cup semi-finals, losing against Porto at the Estádio do Dragão to a late goal from Mariano González. His impact at Académica was immediate, not only because of solid results, but also because of the attractive football displayed by the team, which led to intense media speculation linking him with the vacant jobs at Sporting CP and FC Porto in the summer of 2010.

Villas-Boas signed a deal to become the new manager of Porto on 2 June 2010. Two months later, he won his first trophy as a manager when Porto defeated Benfica 2–0 to win the Portuguese Supercup. Villas-Boas went on to immense success with Porto, leading them to an undefeated season in the Primeira Liga—only the second time this had ever been achieved—and winning the title by more than 20 points, having conceded only 13 goals all season. Villas-Boas went on to follow up this success by leading Porto to win both the Portuguese Cup and the UEFA Europa League, thus completing a treble in his first season in charge. By doing so, Villas-Boas became the third-youngest coach ever to win the Primeira Liga (behind Mihály Siska in 1939 and Juca in 1962) and the youngest manager ever to win a European competition, at the age of 33 years and 213 days. On 21 June 2011, Villas-Boas tendered his resignation as Porto manager.

Chelsea confirmed the appointment of André Villas-Boas as their new manager on a three-year contract with immediate effect on 22 June 2011. They indirectly paid Porto a world record €15 million (£13.3 million) compensation via Villas-Boas to activate his release clause and free him from his contract with Porto. On 30 July 2011, during the pre-season, Villas-Boas won his first piece of silverware with Chelsea, the 2011 Barclays Asia Trophy. Villas-Boas won all of his pre-season fixtures with Chelsea, with the team conceding only one goal in all six games. On 14 August, Villas-Boas’s first Premier League match ended in a 0–0 at Stoke City, with Villas-Boas commenting on Stoke’s strong defence at home. Villas-Boas then won his first competitive match as Chelsea manager, defeating West Bromwich Albion 2–1 on 20 August. He continued his season with a home win, beating Norwich City 3–1. On 18 September 2011, Villas-Boas’s Chelsea lost to Manchester United 3–1 at Old Trafford. It was Chelsea’s first defeat of the season and Villas-Boas’s first defeat in 39 league matches, a run stretching back to his spells as manager of Académica and Porto. On 29 October, Chelsea lost their second derby under Villas-Boas in a 5–3 defeat at home to Arsenal after falling to a 1–0 defeat to Queens Park Rangers. Then three weeks later, his Chelsea side lost a second successive home game in a 2–1 defeat to Liverpool. Days later, he once again lost to Liverpool in a 2–0 defeat in the League Cup quarter-final.

On 11 February 2012, pressure began to mount on Villas-Boas as Chelsea dropped out of the top four in the Premier League following a 2–0 league defeat against Everton. Villas-Boas responded by cancelling his squad’s day off and called them in for an inquest, which provoked several senior players to question his tactics in front of owner Roman Abramovich. On 21 February 2012, during a Champions League match against Napoli, Villas-Boas left Frank Lampard, Michael Essien and Ashley Cole on the bench. Chelsea lost 3–1 and the club’s technical director asked for an explanation of the team selection on behalf of Abramovich. On 4 March 2012, following a 1–0 league defeat against West Brom which left Chelsea three points adrift of Arsenal in the battle for fourth place in the Premier League, Villas-Boas was relieved of his managerial duties by Chelsea, with assistant manager Roberto Di Matteo being appointed as caretaker manager on an interim basis until the end of the season. On the Chelsea website, it read, “The board would like to record our gratitude for his work and express our disappointment that the relationship has ended so early.”

On 3 July 2012, it was announced that Villas-Boas had been named Tottenham Hotspur head coach after successful talks with the club, replacing Harry Redknapp and signing a three-year deal with the North London football team. Villas-Boas’ first competitive game in charge of Tottenham came on 18 August 2012 in the opening day of the Premier League season, losing 2–1 to Newcastle United away from home. His first competitive win came on 16 September 2012, a 3–1 victory away to Reading.

On 29 September 2012, Villas-Boas became the first Tottenham manager to win at Old Trafford in 23 years after his side beat Manchester United 2–3. Villas-Boas took charge of his first North London derby against Arsenal on 17 November 2012 at the Emirates Stadium. Despite taking the lead early on, goalscorer Emmanuel Adebayor was sent off just eight minutes later, and Tottenham eventually lost 5–2. Villas-Boas earned his first piece of personal Tottenham silverware when he won the Manager of the Month award for December. The team managed to pick up vital points in order to pursue their top four ambition. Promising big scorelines away from home such as against Fulham, Aston Villa and Sunderland along with home wins against Swansea City and Reading, left Tottenham in third place going into the new year. One set back was a tough trip to Goodison Park, where Spurs were leading up until the 90th minute, before two late Everton goals in as many minutes, snatched victory away from the North London side.

In February 2013, he guided Tottenham to the last 16 of the Europa League after a last minute goal from Mousa Dembélé, securing a 1–1 draw against Olympique Lyonnais at the Stade Gerland. Spurs won the tie 3–2 on aggregate, after a 2–1 win at home the previous week. Following a 3–2 away win at West Ham United, Tottenham’s third win from three Premier League matches that month, Villas-Boas picked up his second piece of personal Tottenham silverware of the season as he was awarded the Manager of the Month award for February, along with Gareth Bale who picked up the Player of the Month award for February as well.

On 16 December 2013, Tottenham announced that Villas-Boas had left the club “by mutual consent.” The dismissal, with Spurs lying seventh in the Premier League and having won all six of their Europa League group games, followed a series of disappointing domestic league results that included a 6–0 defeat away to Manchester City and culminated in a 0–5 home defeat to Liverpool. Villas-Boas left the club with the highest percentage of league wins of any Tottenham manager in the club’s Premier League era.

On 18 March 2014, Villas-Boas signed a two-year deal with Zenit Saint Petersburg, replacing Luciano Spalletti, and took the reins the day after the club’s Champions League round of 16 second leg against Borussia Dortmund. A month later, he went on to become the first coach in Russian Premier League history to win his first six matches in charge. He continued to pursue the title but on 3 May, Zenit lost their first points in a 1–1 away draw with Lokomotiv Moscow being followed by a 2–4 loss at home to Dynamo Moscow which dictated the league advantage to CSKA Moscow. In the final fixture of the Russian Premier League on 16 May, Zenit won 4–1 away against Kuban Krasnodar but it was not enough to win the title, as CSKA defeated Lokomotiv and were crowned champions one point ahead of Zenit. However, the St. Petersburg club clinched a place in the 2014–15 UEFA Champions League Third qualifying round.

In the 2014–15 season, Zenit qualified for the UEFA Champions League group stage by beating AEL Limassol in the third round qualification and Standard Liège in the playoffs. On 17 May 2015, Villas-Boas led the club to the fifth league title in its history, clinching it after a 1–1 draw against FC Ufa with two games left to play.

On 10 September 2015, Villas-Boas announced he would return to Portugal because of his family and therefore be leaving Zenit at the end of the 2015–16 season after turning down a contract extension. In the 2015–16 Champions League Zenit finished top of the Group H, being eliminated by Benfica in the Round of 16. On 2 May 2016, Zenit won the Russian Cup by beating CSKA Moscow 4–1 in the final in Kazan, this was the Portuguese last achievement for the Russian side, leaving at the end of the season and with Mircea Lucescu appointed the new manager.

On 4 November 2016, Villas-Boas became the manager of Shanghai SIPG, replacing Sven-Göran Eriksson for the Chinese Super League club. Despite not being able to win any major silverware during his stint at the club, Villas-Boas has been credited with turning a relatively inexperienced side into a true championship contender. Bolstered by the talents of Brazilians Hulk and Oscar as well as star Chinese attacker Wu Lei, his only season at the helm saw SIPG finish second in the league, losing to rivals Shanghai Shenhua in the final of the Chinese FA cup, as well as reaching the semi-finals of the Asian Champions League, the club’s best result in the competition to date (as of November 2019).

On November 2017, Shanghai SIPG announced Villas-Boas left the club by mutual consent after he refused to extend his contract for another year.

On 29 November 2017 it was announced that Villas-Boas would compete in the 2018 Dakar Rally driving a Toyota Hilux and co-driven by former motorcycle class frontrunner Ruben Faria. He withdrew from the rally after crashing into a sand dune on the fourth stage in Peru and damaging his back.

On 28 May 2019, Villas-Boas signed a two-year contract to be the new manager of Marseille, replacing Rudi Garcia.