Paltrinieri started swimming at a very young age, and until the age of 12, he specialized in breaststroke. However, as he grew, he converted to freestyle, specializing in the longer pool distances.
His first international success came as a 16-year-old at the 2011 European Junior Swimming Championships in Belgrade, where he won the 1500 metres gold and an 800 metres bronze. Having qualified for the World championships in Shanghai, he did not progress further than the heats, but a few weeks later at the World Junior Championships in Lima, Peru, he was back on the podium with a 1500 metres freestyle silver and an 800 metres bronze.
In March 2012 Paltrinieri won the Italian 800 metres freestyle title, and two months later, he left everyone in his wake at the European Championships in Debrecen, defeating renowned Hungarians Gergő Kis and Gergely Gyurta in the 1500 m. His time of 14:48.92 qualified him for the Olympics and, at the time, was the year’s second-fastest 1500 m swim, breaking the championship record. He is trained by Stefano Morini. At 2012 Summer Olympics, the 17-year-old Italian advanced to his first Olympic final with the 4th fastest time of 14:50.11. In the final he finished 5th in 14:51.92.
At the end of 2012 Paltrinieri finished 2nd in the 1500 meter freestyle event at the 2012 FINA World Swimming Championships (25 m), and was later awarded a gold medal after a positive doping test for Danish swimmer Mads Glæsner. However, upon appeal to the Court of Arbitration for Sport, Glæsner's 1500-meter freestyle gold medal was reinstated based on the fact that a test after that race, two days after his initial positive test following the 400-meter free, was clean. This means that Paltrinieri was returned to his silver medal position in the 1500 m freestyle.
Paltrinieri competed for Italy at 2013 World Aquatics Championships. He reached his first 800 metres freestyle final at a long course world championship event finishing sixth in 7:50.29. In the 1500 metres freestyle event Paltrinieri won a bronze medal with a time of 14:45.37, establishing a new national record.
In 2014 Paltrinieri at the Italian Swimming Championships in Riccione finished second in 800 metres freestyle event with a time of 7:43.01, behind Gabriele Detti who established a new European record in the distance. Three days later Paltrinieri established a new national record of 14:44.50 in the 1500 m freestyle event. The day before the meet, Paltrinieri had swum an unofficial world best time of 50:56.50 in the 5 km (long course pool) at the Italian indoor distance championships in Riccione.
In August, at the 2014 European Aquatics Championships, Paltrinieri won the 800 m and 1500 m freestyle events establishing the new European record of 14:39.93; with this result he became only the fifth swimmer ever to swim under 14:40.00 in the 1500 m freestyle long course. At the 2014 FINA World Swimming Championships (25 m) in Doha, Paltrinieri became World champion for the first time with the new European record of 14:16.10, which was also the second fastest time ever swum behind Grant Hackett's world record.
At the 2015 World Aquatics Championships, in Kazan, Paltrinieri won the silver medal in the 800 m, losing to Sun Yang. Later he won the 1500 m, setting a new European record, a race in which Sun did not take part despite having qualified for the final with the second best time after Paltrinieri.
At the end of the year Paltrineri took part at the 2015 European Short Course Swimming Championships in Netanya (Israel); here he established a new 1500 metres freestyle world record of 14:08.06 winning the gold medal ahead fellow Italian and friend Gabriele Detti. The previous record set in 2001 by Grant Hackett was beaten by 2.04 seconds. With the gold medal, Paltrinieri also became the simultaneous holder of the world and European titles, in long course and short course, in the 1500 metres freestyle event.
At the 2016 Rio Olympics Paltrinieri won the gold medal in the 1500 m freestyle in a time of 14:34.57, having qualifying fastest for the final.
In 2017, Paltrinieri confirmed his World Championship gold medal in the 1500m freestyle at the 2017 World Aquatics Championships held in Budapest. He also won a bronze medal in the 800m race, won by fellow Gabriele Detti.As of 5 December 2015