In 1997, Melandri won the Italian 125cc championship, also finishing 4th in European 125cc championship. In addition to his European success, he made his debut in 125cc world championship at Brno, Czech Republic as a wild card rider.
After impressing in Italian and European championship in 1997, Melandri finally got his chance to compete in 1998 125cc world championship as a regular. He rode Honda 125cc bike under Benetton Honda Team. He went on to impress many as he earned his first podium in the fourth race of the season, where he finished second in his home Grand Prix at Mugello, Italy. His brilliant debut season continued when he won his first grand prix at Assen TT, Netherlands. He won this race at the age of 15 years and 324 days which made him the youngest ever Grand Prix winner, at the time. Overall, he won two Grand Prix in his debut season and therefore he finished the season at 3rd position in overall standings behind champion Kazuto Sakata and runner-up Tomomi Manako.