Almagro won the gold medal at the 2005 Mediterranean Games by defeating compatriot Guillermo García López in the final in Almería, Spain.

In April 2006, Almagro won his maiden ATP tournament title, the Open de Tenis Comunidad Valenciana (Valencia, Spain).

Almagro was forced to come through the qualification rounds just to make this event, but that did not stop him from winning eight matches in a row, including three-set victories over former world number ones Juan Carlos Ferrero and Marat Safin.

He did show signs of improving his hardcourt game by making a quarterfinal indoors in Lyon, and he also won matches at the Masters 1000 events in Cincinnati and Paris.

He reached the semifinals of Buenos Aires, the finals of Båstad, and began to show promise on hard courts also, advancing to the quarterfinals of the Masters 1000 event in Cincinnati and the third round of the US Open (losing to Davydenko).

In 2008, Almagro won the third title of his career in Costa do Sauipe by defeating Carlos Moyá in a rollercoaster three-set battle.

He achieved his best Grand Slam result in June by reaching the quarterfinals of the 2008 French Open, where he lost to Rafael Nadal, 1–6, 1–6, 1–6.

During his run, he beat Boris Pašanski, Sebastián Decoud, tenth seed Andy Murray, and home-favourite Jérémy Chardy in straight sets.

The fourth seed at the event, Almagro received a bye into the second round, where he defeated Lu Yen-hsun of Taiwan in three sets.

This gained him entry into the quarterfinals, where he was defeated in straight sets by American Sam Querrey, sixth seed at the event.

At the 2009 Brasil Open, where Almagro was the defending champion and top seed, he lost in the quarterfinals to Frederico Gil in two tiebreak sets, 6–7, 6–7.

Almagro played the whole tournament with a broken left wrist, preventing him from exceeding 200 km/h when serving due to an altered ball-toss.

He was ousted in the opening round of the 2010 Copa Telmex tournament for the second straight year (losing to Gimeno Traver).

In the Monte Carlo Rolex Masters 1000, he beat Simon Greul before falling to Jo-Wilfried Tsonga in the second round.

Almagro then bowed out in straight sets in the quarterfinals, losing a closely contested match against eventual champion Rafael Nadal, 6–7, 6–7, 4–6.

He won the tournament after defeating compatriot Marcel Granollers, 7–6, 3–6, 6–3, Swiss wildcard Michael Lammer, 3–6, 6–3, 6–2, Frenchman Jérémy Chardy, 6–2, 7–6, and then another fellow Spaniard Daniel Gimeno Traver, 7–6, 3–6, 6–3.

He easily cruised to the semifinals, and after a slow start, he defeated Juan Ignacio Chela, 1–6, 6–2, 6–4, to reach the final.

His winning streak continued as he snatched his second consecutive title in as many weeks at the 2011 Copa Claro tournament in Buenos Aires, Argentina, defeating Juan Ignacio Chela, 6–3, 3–6, 6–4, in the final.

His hot streak stretched even further at the 2011 Abierto Mexicano Telcel tournament in Acapulco, Mexico, making his third consecutive clay-court final.

Almagro then appeared at the 2011 Barcelona Open Banco Sabadell, where he notched a 7–5, 7–6 win over in-form compatriot Pablo Andújar.

Almagro played Julien Benneteau in the first round of the US Open, making many unforced errors and only managing to break once out of 13 chances.

In February, Almagro earned his 11th career title in São Paulo, defeating Filippo Volandri in the final.

Almagro got his revenge at Indian Wells, where he beat and bageled Berdych in the fourth round to advance to the quarterfinals, where he met Novak Djokovic.

However, during the 2012 London Olympics, he made a surprising run to the quarterfinals without dropping a set, before losing 4–6, 1–6 to eventual champion Andy Murray.

[7] Almagro reached the quarterfinals of the Australian Open for the first time, where he played compatriot David Ferrer, whom he had never beaten in twelve previous meetings.

Almagro then reached the fourth round of the French Open where, for the second Grand Slam running, he lost after leading by two sets and a break against a compatriot, this time Tommy Robredo.

Almagro reached the semifinal stage of the bet-at-home Open in Hamburg, losing to Fabio Fognini in straight sets.

At the Barcelona Open Banc Sabadell, he defeated Martin Kližan and Fernando Verdasco, then snapped Nadal's 41-match winning streak.

At Roland Garros, Nicolás was forced to retire in the first round against American Jack Sock due to a foot injury.

In the 2012 Davis Cup final, he lost to Tomáš Berdych and again to Radek Štěpánek in the fifth rubber, denying Spain a repeat win.