Malignaggi was born in Brooklyn, United States to Sicilian immigrant parents. He spent most of his early days in Syracuse, Sicily. Six years later, after Malignaggi's brother Umberto was born, the family decided to settle back in Brooklyn, but Malignaggi's father stayed for only a few weeks before returning to Italy. Malignaggi's mother remarried. The two brothers reputedly did not get along with their new stepfather. In 1996, the pair got into a fight with their stepfather. Not long after, the brothers left the house. Malignaggi then lived with his grandparents until he got his own home years later. Malignaggi used to violate school rules. He regularly got involved in street fights, using knives and sometimes guns. He was eventually expelled from high school for street fights and ditching classes. His grandfather took him to work each day until Malignaggi asked that he be allowed to take up boxing. He was given the chance, marking Malignaggi's transition into boxing.
Upon turning pro in 2001, Malignaggi won his first 21 fights before suffering his first loss in a grueling battle with multiple-division champion Miguel Cotto in June 2006.
Malignaggi got back on track with a unanimous decision victory over Edner Cherry at the Hammerstein Ballroom in New York City, February 17, 2007.
On June 16, 2007, Malignaggi defeated Lovemore N'dou via a 12 unanimous decision to win the IBF Light Welterweight Championship at the Mohegan Sun Casino in Uncasville, Connecticut. The bout was one sided with one judge awarding the bout a 120–106. Lennox Lewis, who was commentating at ringside for HBO, described Malignaggi's performance as a "boxing clinic." After this win and the victory over Edner Cherry earlier in the year, Malignaggi was awarded the Ring Magazine comeback of the year award at the end of 2007.
On January 5, 2008, Malignaggi defended his title against Herman Ngoudjo in a highly competitive match held at Bally's Casino in Atlantic City, New Jersey. Malignaggi controlled the fight with his jab until he was stunned in the 7th round, but Ngoudjo failed to finish the job. After the seventh, Ngoudjo became ineffective with his aggression and came up short and lost a wide unanimous decision, which although fair, did not reflect the competitiveness of the fight.
On May 24, 2008, Malignaggi beat Lovemore N'Dou in a rematch by split decision to retain his IBF title at the City of Manchester Stadium in Manchester, England. Malignaggi was in control for the first half of the fight, boxing behind his faster and crisper jab. Prior to the fight, Malignaggi was sporting hair extensions which proved to be a problem throughout the fight until his trainer Buddy McGirt cut them off in his corner between rounds eight and nine. Malignaggi appeared sloppy in the second half of the fight as N'Dou came back to make the fight close. In the end, Malignaggi pulled out a close victory and also suffered a fractured right hand in the fight. Malignaggi vacated his title on September 19, 2008.
On November 22, 2008 in the MGM Grand Garden Arena in Las Vegas, Malignaggi fought The Ring and IBO Light Welterweight Champion Ricky Hatton. It was billed as the boxer against the brawler. Hatton dominated and won every round but the first. Hatton rocked Malignaggi in the second and several other times during the fight, leaving Paulie to hold on, doing exactly what Malignaggi had publicly criticized Hatton for doing, while promoting the fight. With Malignaggi way behind on points, his trainer Buddy McGirt threw in the towel during the 11th round.
On August 22, 2009 at the Toyota Center in Houston, Texas. Malignaggi fought former lightweight titlist Juan Díaz for the vacant WBO NABO Light Welterweight title at a catch-weight of 138½ pounds. Unofficial HBO scorer Harold Lederman scored the fight 115–113 for Malignaggi, but none of the three judges saw the fight this way. Gale Van Hoy had it by an 118–110, Raul Caiz had it 115–113 and the other Judge, Dave Sutherland scored it 116–112, all in favor of Juan Díaz. In the post fight interview of the Juan Díaz fight (interviewed by Max Kellerman, HBO boxing analyst), Paulie was furious, stating that "boxing is full of shit." He also stated that the only reason he is continuing to fight is because of the good pay day.
A rematch with Juan Díaz occurred on December 12, 2009 in Chicago on HBO. This rematch went in Malignaggi's favor when he defeated Juan Díaz by unanimous decision. All three judges scored the fight 116–111 in favor of Malignaggi. In the fight, Malignaggi threw more punches but only landed 21% of them while Diaz landed 28% of his, but threw fewer.
Malignaggi's next fight was against Amir Khan in Madison Square Garden in New York on May 15, 2010. The press conference took place in London on March 12 while another press conference was held in New York City, United States on March 16. Malignaggi was stopped in the eleventh round by the referee. As the fight progressed, Malignaggi began to fall behind on points and the result began to get comfortable for Khan. He was very overmatched throughout the fight. This would be his last fight at Jr. welterweight, he had a very difficult time making weight for this fight and it showed in his performance. On September 28, 2010 it was announced that Malignaggi signed with Golden Boy Promotions.
On April 29, 2012 Malignaggi fought WBA Welterweight Champion Viacheslav Senchenko in Donetsk, Ukraine. Malignaggi won by ninth-round technical knockout to take the title.
Malignaggi then went on to defeat Pablo César Cano via split decision on October 20, 2012, on the undercard of Erik Morales and Danny Garcia rematch.
Malignaggi then went on to fight Adrien Broner on June 22, 2013. Malignaggi lost a split decision, with one judge scoring the fight 115-113 for Malignaggi, and the other two scoring 117-111 and 115-113 for Broner.
Malignaggi then faced five-time champion and fellow Brooklyn native Zab Judah at the Barclays Center in Brooklyn, New York on December 7, 2013. In the second round, after Judah connected with a hard left hand, Malignaggi went down but argued that it was a slip. Malignaggi got up and went to dominate the remainder of the fight en route to a unanimous decision victory.
Entering the fight as a 2-to-1 underdog, Malignaggi faced Shawn Porter at the DC Armory in Washington, D.C. on April 19, 2014. Malignaggi was cut in the first round by a Porter double-jab, and was knocked down early in the fourth round before being defeated by TKO at 1:14 in the same round.
Malignaggi took on Danny García at Barclays Center, Brooklyn, August 1, 2015. It was Malignaggi's first step up to fight at 147 lbs. Malignaggi was cut above his right eye by the third and had a large welt beneath the right eye by the sixth. At the time of the stoppage, at the 2:22 mark of the ninth round, Malignaggi was absorbing a succession of blows as referee Arthur Mercante Jr. stepped in and wrapped his arms around him, signaling the end. Garcia was awarded a technical knockout.
Following the loss to Garcia, Malignaggi wasted no time to return to the ring a month later, fighting in Italy for the first time in his career against little-known 25 year old Hungarian boxer Laszlo Fazekas. In front of a sold out crowd of 550, at the Teatro Principe in Milan, Malignaggi who won on points after 8 rounds. The three judges had it (79-72, 80-71, 80-71) for Malignaggi. Fazekas showed signs of dirty tactics and paid the price by being deducted a point in round 3 for hitting with inside of the glove.
Malignaggi returned to the boxing ring again in December against Italian boxer Antonio Moscatiello (20-2-1, 14 KOs) on the undercard of Joshua-Whyte at the O2 Arena in a 12-round scheduled fight for the vacant EBU welterweight title. Malignaggi was supposed to fight 47-year-old Gianluca Branco, however that fell apart after Branco reportedly pulled out of the fight. The fight went the full 12 rounds as Malignaggi claimed a wide points victory on all three judges scored it 119-110, 119-110 and 120-109.
According to ESPN, reports stated Malignaggi would be fighting 35-year-old Gabriel Bracero (24-2, 5 KOs) on the undercard of the Leo Santa Cruz vs. Carl Frampton fight card on July 30 at the Barclays Center in Brooklyn, New York. Malignaggi defended his 'King of Brooklyn' belt and local bragging rights. Using rapid footwork and moving in and out, Malignaggi won the first eight rounds as Bracero stood in front of him not moving or chasing or changing strategy. The final judge’s scores were 96-94, 98-92 and 98-92. After the bout, Malignaggi returned to commentating at ringside.
On January 25, 2017 it was announced that Malignaggi would travel to the UK to challenge 23 year old Sam Eggington (19-3, 11 KOs) for his WBC International welterweight title on the Haye-Bellew PPV undercard on March 4 at The O2 Arena. Referee Laughlin called it at 1 minute 50 seconds into round 8 with Eggington winning the fight by way of knockout. The came to an end when Eggington landed a body shot on Malignaggi causing him pain. This followed with a short right to the head. At the time of the stoppage, Malignaggi was ahead on two of the judges scorecards. Malignaggi said he would be retiring with this being his last fight.
On March 6, 2017 Malignaggi officially announced his retirement from boxing at the age of 36, calling an end to his 16-year professional career. Malignaggi wrote on social media, "Nineteen years ago today, I entered the ring for the first time as an amateur. That makes this as good a time as any to announce my retirement from competition." He finished his career with 44 professional fights, winning 36, with 7 inside the distance and 8 losses.
In retirement, Malignaggi joined the Team McGregor camp following the announcement of Conor McGregor's August 26, 2017 boxing bout against undefeated Floyd Mayweather. A sparring session between Malignaggi and McGregor was rumored to have become violent, and photos were leaked showing Malignaggi appearing to have been knocked down. Malignaggi disputed the rumors and announced on Aug. 3, 2017 he would be leaving Team McGregor. He also called for the full video of the sparring session to be released to show what actually took place, claiming he was pushed and never knocked down during the 12 round session. He also claimed that in fact over the 12 rounds of sparring he had dominated Conor McGregor. On August 11, two short clips of the sparring session, including of the knockdown in question, were released by Dana White on Instagram. This footage showed McGregor as the aggressor and landing multiple shots against Malignaggi, who after the release continued to assert he had been pushed, citing McGregor's hand placement holding his neck down prior to swinging a left uppercut and pushing off with his right hand.
Malignaggi has featured in print clothing advertisements that have been published in magazines such as Esquire and Playboy. He also had a small role in the 2003 film Undefeated, and had a feature documentary on his life leading up his fight with Miguel Cotto, entitled Magic Man, which later aired on Showtime. Video game company Nintendo used Malignaggi to portray their character Little Mac in the live-action trailer for the 2009 game Punch-Out!! for the Wii. Also in 2009, he was a featured fighter in EA Sports' Fight Night Round 4. Malignaggi is currently an award-winning boxing commentator for Showtime, Fox Sports 1, and British network Sky Sports. In 2015, Malignaggi featured in the Blue Bloods episode "Home Sweet Home".