From 1997 to 2000, Paul-Henri trained at the IMG Bollettieri Tennis Academy in Bradenton, Florida before moving back to Paris.

Mathieu won the boys' singles title at the 2000 French Open, defeating Tommy Robredo 3–6, 7–6(7–3), 6–2 in the final.

Mathieu made his ATP World Tour singles main draw debut in July 2000 in the Austrian town of Kitzbühel.

He made the fourth round of the French Open, losing to Andre Agassi in five sets, despite having a two-set lead.

Many tennis players and commentators, including two-time French Open runner-up Àlex Corretja, hailed it as a classic.

2007 started poorly for Mathieu when he injured himself at the Australian Open during a 1st round encounter against Spaniard Fernando Verdasco and was forced to retire from the match.

After returning from his injury, he reached the 4th round in Miami, beating then world number 5 Fernando González of Chile along the way, before bowing out to Andy Murray in 3 sets.

On 29 April 2007, Mathieu won his 3rd career title, the Grand Prix Hassan II in Casablanca defeating Álbert Montañés 6–1, 6–1.

The week after Wimbledon, he beat Italian Andreas Seppi 6–7, 6–3, 7–5 in a difficult final to claim his fourth ATP Tour title in Gstaad, Switzerland.

[4] At the 2015 Generali Open Kitzbühel, Mathieu reached the final as a qualifier, after wins over Kenny de Schepper, Martin Kližan, Federico Delbonis and Nicolás Almagro.

265 in the ATP singles rankings coming into the tournament, he lost in the second and final singles qualifying round to Vasek Pospisil; he and his partner Benoît Paire lost in the doubles main draw first round to the American pair of Nicholas Monroe and Jack Sock.

A relatively popular, well-liked player despite his inconsistent career results, Mathieu is nicknamed "Paulo" and often affectionately known by his initials, PHM.

[1] On 11 March 2012, Paul-Henri Mathieu became a father for the first time when his girlfriend, Quiterie Camus, gave birth to the couple's first child, a son named Gabriel.