Rafter turned professional in 1991. He twice won the men's singles title at the US Open and was twice the runner-up at Wimbledon. He was known for his natural serve-and-volley style of play. Rafter was on the Australian Davis Cup Team that lost in the final in 2000 (to Spain) and 2001 (to France). He was unable to play in the 1999 Davis Cup final – where Australia beat France to win the cup – because of injury (though he won important matches in the earlier rounds to help the team qualify).

Rafter won his first tour level match in 1993, at Wimbledon. He reached the third round, before losing to Andre Agassi. He also reached the semifinals in Indianapolis. He defeated Pete Sampras in the quarterfinals in three tight sets, before losing to Boris Becker in the semifinals. Rafter finished 1993 with a ranking of 66.

Rafter won his first career singles title in 1994 in Manchester. Prior to 1997, this was the only ATP singles title he had won.

Rafter donated half of the prize money from his 1997 and 1998 US Open wins to the Starlight Children's Foundation; he attempted to do so anonymously in 1997 but was unsuccessful. He has created his own charity organisation that raises funds for children's causes each year. Rafter also supports animal rights and the work of animal liberation groups such as makeitpossible.com.

Rafter then defended his U.S. Open title by defeating fellow Australian Mark Philippoussis in four sets, committing only five unforced errors throughout the match. When asked about Sampras' earlier comments about having to win another Grand Slam in order to be considered great, Rafter replied: "Maybe you can ask him that question, if he thinks that now. For me, I won another Slam, and it hasn't sunk in yet. It's very, very exciting for me, especially to repeat it". Altogether, Rafter won six tournaments in 1998, finishing the year #4 in the world.

At the 1999 French Open, Rafter drew Future World No. 1 and 20-time Grand Slam champion Roger Federer in the first round, making him the first ever opponent of Federer in the main draw of a Grand Slam tournament. Rafter defeated him in four sets, after losing the first set. Rafter then reached the Wimbledon semifinals for the first time in 1999, where he lost in straight sets to Agassi, the first of three consecutive years that the two met in the Wimbledon semifinals. July 1999 saw Rafter holding the world No. 1 men's singles ranking for one week, making him the shortest-reigning world No. 1 in ATP tour history. As the two-time defending US Open champion, Rafter lost in the first round of the tournament, retiring in the fifth set against Cédric Pioline after succumbing to shoulder tendinitis. Rafter's shoulder injury wound up being serious enough to necessitate surgery. He won the Australian Open men's doubles title in 1999 (partnering Jonas Björkman), making him one of few players in the modern era to win both a singles and doubles Grand Slam title during their career (fellow countryman Lleyton Hewitt would later achieve this feat in 2001). He and Björkman also won doubles titles at the ATP Masters Series events in Canada (1999) and Indian Wells (1998).

His ranking had fallen to No. 21 by the time he reached the Wimbledon final in July 2000. In the semifinals, Rafter defeated Agassi 7–5, 4–6, 7–5, 4–6, 6–3. The match was hailed as a classic, particularly because of their contrasting playing styles, with Agassi playing primarily from the baseline and Rafter attacking the net. Rafter faced Sampras in the final, who was gunning for a record-breaking seventh Wimbledon title overall (and seven in the past eight years). While Rafter made a strong start to the match and took the first set, after the match he would claim that he had "choked" part way through the second set, and was then not able to get back into his game. Sampras won in four sets.

In 2001, Rafter reached the semifinals of the Australian Open, but despite holding a two sets to one lead and having the support of the home crowd, Rafter lost the match to Agassi in five sets. Later in the year, Rafter again reached the Wimbledon final. For the third straight year, he faced Agassi in the semifinals and won in yet another five-setter, 2–6, 6–3, 3–6, 6–2, 8–6. Much like the previous year's semifinal, this match also received praise for the quality of play that the two men displayed. In the final, he squared off against Goran Ivanišević, who had reached the Wimbledon final three times before but had slid down the rankings to World No. 125 following injury problems. In a five-set struggle that lasted just over three hours, Ivanišević prevailed. He played his last match before his unexpected retirement at the Davis Cup final, winning the singles rubber but losing the doubles rubber.

In honour of Patrick Rafter the 5,500 seat centre court of the Queensland Tennis Centre in Brisbane, Australia was named Pat Rafter Arena. In 2002, he won the Australian of the Year award. This created some controversy as he had spent much of his career residing in Bermuda for tax purposes.

In April 2004, Rafter married his girlfriend Lara Feltham (with whom he had a son, Joshua) at a resort in Fiji. Their daughter, India, was born in May 2005.

He was elected to the International Tennis Hall of Fame and inducted into the Sport Australia Hall of Fame in 2006. On Australia Day 2008, Pat Rafter was inducted into the Australian Open Hall of Fame.

In 2009 as part of the Q150 celebrations, Pat Rafter was announced as one of the Q150 Icons of Queensland for his role as a "sports legends".

Rafter, while professional, used Prince Sports racquet and Reebok clothes. Since the beginning of 2011, he began using Dunlop Sport racquet, continuing with Reebok clothes.

On January 12, 2014 Rafter, aged 41, announced that he would be partnering current Australian number one Lleyton Hewitt in the doubles draw of the 2014 Australian Open. The comeback, however, was short-lived as the pair went down in straight sets to eventual runner-ups Eric Butorac and Raven Klaasen in the first round.

In October 2010 he was announced as Australia's Davis Cup captain. Rafter stood down as Australia's Davis Cup captain on 29 January 2015. He was succeeded by Wally Masur.