Manzi joined the Red Bull MotoGP Rookies Cup in 2012, immediately showing podium ability with a second place at the Sachsenring and a third at Brno in his debut season, finishing 13th overall with 75 points. He returned in 2013 and 2014, finishing third in the championship in both years. In 2013 he took four second places and three thirds; in 2014 he added his first Rookies Cup victory alongside two second places and six third-place finishes.
Manzi entered the 2015 Moto3 World Championship with San Carlo Team Italia from the second round, missing the opener due to age restrictions. He rode a Mahindra MGP3O alongside Matteo Ferrari, scoring points four times with a best of twelfth in Aragon and closing the year 27th on 10 points. He made three wildcard appearances in 2016 with Mahindra Racing, scoring 13 points — all from a fourth place at Silverstone.
Manzi stepped up to Moto2 in 2017 with Sky Racing Team VR46 alongside Francesco Bagnaia, riding a Kalex. He scored points four times and achieved a best of seventh at Silverstone, finishing 25th with 14 points.
For 2018 he switched to Forward Racing in a swap with Luca Marini. The season is remembered primarily for an incident at Misano: Romano Fenati reached over and grabbed Manzi's front brake lever at 200 km/h during the race, causing Manzi to crash after momentarily holding his machine. Fenati was black-flagged, disqualified, and ultimately had his contract terminated. Manzi returned for the following two rounds but declined to race once Fenati served his ban, stating he did not feel safe on track with riders who had endangered his life. He finished 24th with 8 points.
Manzi remained with the team — rebranded MV Agusta Forward Racing — for 2019 and 2020, riding MV Agusta machinery. In 2019 he had seven points-scoring finishes and reached fourth in Valencia, closing 19th with 39 points. The 2020 season brought his first Moto2 pole position at Valencia, the first pole for Forward Racing since 2010 and the first for MV Agusta in 44 years. He finished 22nd with 21 points.
His final Moto2 campaign in 2021 came with Pons Racing (Flexbox HP40), partnered by Héctor Garzó. Seven point-scoring results including a sixth at Misano produced 36 points and 19th in the standings.
After a brief spell with Yamaha VR46 Master Camp Team in 2022, Manzi entered the Supersport World Championship with Dynavolt Triumph that same year and built steadily toward the front. His trajectory culminated in the 2025 WorldSSP title with Ten Kate Racing, establishing him as the championship's premier contender. For 2026 he was promoted to World Superbike with the GYTR GRT Yamaha factory satellite team.
Manzi's career is defined by resilience. The Fenati incident at Misano in 2018 — one of the most condemned acts in modern motorcycle racing — threatened to overshadow his development as a rider, but his principled response and continued progress through the WorldSSP ranks demonstrated both character and competitive longevity. The 2025 world title confirmed him as one of the most effective Italian racers of his generation in production-based competition.