Born in Madrid, Manquillo started playing football with hometown's Real Madrid alongside his twin brother Víctor, a forward. However, in mid-2007, the club decided to release the latter and the former followed suit, with both signing for neighbouring Atlético Madrid 48 hours later. In November 2011 he made his unofficial debut with first team, playing in a friendly game against Zamalek SC; late into the month, he extended his contract until 2016. On 8 December 2011, Manquillo made his official debut for the Colchoneros, starting in a 1–2 away loss against Albacete Balompié in the Copa del Rey. He was subsequently an unused substitute in the matches against Real Sociedad and Málaga CF, whilst finishing the season in Segunda División B with 13 appearances for the B-side. On 28 November 2012, again in the domestic cup, Manquillo appeared in his second game with Atlético's main squad, playing 63 minutes in a 3–0 success at Real Jaén. On 6 December he featured in the 0–1 away defeat against FC Viktoria Plzeň in the 2012–13 UEFA Europa League. Manquillo's debut in La Liga came on 9 December 2012, coming on for Filipe Luís late into the second half of a 6–0 home routing of Deportivo de La Coruña. On 3 September of the following year he signed a contract extension with Atlético Madrid, keeping him at the Vicente Calderón Stadium until 2018. On 11 February 2014, in the first half of the Spanish Cup semifinal clash against Real Madrid, Manquillo was involved in two incidents with Cristiano Ronaldo: in the early minutes, he conceded a penalty which the Portuguese converted in the first goal of an eventual 2–0 win. Later, after both went for an aerial challenge, he fell headfirst to the ground, going on to be sidelined for more than one month with a neck injury. On 6 August 2014, Manquillo joined Liverpool in a two-year loan deal with an option to buy after his first season. He made his debut 11 days later, playing the full 90 minutes in a 2–1 Premier League win over Southampton. On 16 September, he won a 93rd-minute penalty in the UEFA Champions League tie against PFC Ludogorets Razgrad, which Steven Gerrard converted to make the score 2–1 and win the match; the following weekend, in the third round of the Football League Cup, he converted his penalty shootout attempt against Middlesbrough as his team prevailed 14–13 following a 2–2 draw. On 6 January 2015, Manquillo provided the assist for the first of Gerrard's two goals in a 2–1 win at A.F.C. Wimbledon in the FA Cup. After featuring in 16 matches during the first part of the season, he played just three times in 2015, never in the domestic league, and Atlético Madrid subsequently confirmed that the loan deal had been terminated. On 27 July 2015, Manquillo joined Olympique de Marseille on a season-long loan with an option to buy. On 25 August of the following year, still owned by Atlético, he signed with English club Sunderland also for one season.
Newcastle United
On 21 July 2017, Manquillo signed for Premier League club Newcastle United on a three-year contract for an undisclosed fee.
