Pellegrini competed at the 2005 Montreal, where she got a silver in the 200 m freestyle, just behind Solenne Figuès, after being the favourite in the event, because of setting previously the best time of the season in the distance.

Then she competed also at the 200 m freestyle, where, in the semi-finals, she set her first world record of her career, with a time of 1:56:47, beating the previous one belonging to Franziska van Almsick.

But it was beaten the day after in the final by her rival Laure Manaudou, who got the gold medal and immediately broke her world record, while she got just the bronze, behind Annika Lurz too.

Pellegrini's first long course (50 meters) gold medal came at the 2008 European Championships in Eindhoven, where she won the 400 m freestyle setting a world record (4:01.53).

Two days later, she won the gold medal in the 200 m freestyle too with a time of 1:55:58, becoming the first female swimmer ever to win this title at two consecutive editions of the World Aquatics Championships; after the success in Shanghai, she parted ways with her French coach and began working with Federico Bonifacenti.

Anyway, with a last-minute decision, Pellegrini took part to 200 metres freestyle event at the 2013 World Championships and eventually won a silver medal with a time of 1:55.14, her best since Rome.

Eventually, she stated that failing to win an Olympic medal in the women's 200 metres freestyle final in Rio de Janeiro was so devastating for her that she may consider "making changes to her life".

[12] Nevertheless, she got a prime redemption at the World Short Course Championships in Windsor (Ontario), because she won her first gold medal in the 200 freestyle, beating Katinka Hosszú.

[14][15] At the World Aquatics Championships held in Budapest, she won the gold medal in 200 metres freestyle ahead of both Katie Ledecky and Emma McKeon with a time of 1:54.73.

After winning her seventh consecutive medal at the World championships of Budapest 2017 Pellegrini decides to allow herself a sabbatical with milder training and partial abandonment of her beloved 200m freestyle.

[16] Pellegrini won the gold medal (her fourth overall) in the 200 m freestyle race at the 2019 World Aquatics Championships held at Gwangju, with a time of 1:54.22, before Ariarne Titmus and Sarah Sjöström, taking advantage of Katie Ledecky, Emma McKeon and Taylor Ruck's withdrawals in the event, and so improving her record of being the one, among female and male swimmers, to achieve eight podiums in the same event during eight consecutive editions of the World Championships earning the title of 9th-most decorated swimmer history with individuals medals alone.

[21][22] In August 2015 a section of the Lungomare delle Stelle of Jesolo was named after Federica Pellegrini and, as per tradition, the cast of the athlete's hands was made, preserved in the museum Kursaal of the city.

[25] In September 2024 she participated in "Ballando con le Stelle" Italy's version of Dancing with the Stars with her partner dancer Angelo Madonia.

Her personal bests are (as of 15 December 2019): Pellegrini won 129 national swimming championships (both individual and relay races), in absolute (24), winter (38) and spring (66) editions[33]