The circuit was designed in 1969, built between 1970 and 1972, and inaugurated for competition in 1972 at an initial length of 3.488 km. In its early form the facility featured only a small, open pit area and modest infrastructure. The circuit ran counter-clockwise, which is the reverse of its current configuration. This original direction and layout became the identity of Misano for its first three decades of operation.
The first major modification came in 1993, when the track length was extended to 4.060 km. New facilities, pit garages, and stands were added at this time. The 1993 extension created a longer loop while retaining the original counter-clockwise direction, and it also allowed the circuit to be run in both the longer and the older short loop configurations.
Under its pre-2006 layout, Misano hosted the San Marino motorcycle Grand Prix on three occasions: in 1985, 1986, and 1987. These rounds were part of the 500cc World Championship, the premier class of the day, and represented the circuit's first appearances on the world championship calendar. The counter-clockwise layout in use during these events was the version raced by the top competitors of that era.
The most significant incident at the pre-2006 circuit occurred on 5 September 1993. During the Italian Grand Prix — raced on the extended layout introduced that year — defending 500cc World Champion Wayne Rainey fell and suffered a spinal fracture that ended his career and left him paralyzed from the chest down. Rainey had been leading the race at the time of the crash. The accident remained among the defining tragedies of Grand Prix motorcycle racing and contributed to ongoing discussions about circuit safety throughout the decade.
To meet the safety and technical requirements needed to re-host a MotoGP World Championship round, the circuit was extensively rebuilt in 2006. The direction of travel was reversed from counter-clockwise to clockwise. The total circuit length was adjusted to 4.180 km. Track width was widened to 14 metres, and all facilities were upgraded to meet current FIM safety standards. This reconstruction fundamentally changed the character of the venue, and the pre-2006 counter-clockwise layout effectively ceased to exist as a competitive configuration.
The first MotoGP race held under the new clockwise configuration was the 2007 San Marino and Rimini Riviera motorcycle Grand Prix, won by Ducati. This returned world championship motorcycle racing to Misano after a 20-year absence following the three 1985–1987 rounds.
The post-2006 circuit was the site of the death of Japanese Moto2 rider Shoya Tomizawa during the 2010 San Marino and Rimini Riviera motorcycle Grand Prix, when Tomizawa lost control of his bike and was struck by both Scott Redding and Alex de Angelis. The incident occurred on 5 September 2010 — 17 years to the day after Wayne Rainey's crash on the same circuit in 1993.
In November 2011, the circuit owners announced the venue would be named after Marco Simoncelli, an Italian motorcyclist from nearby Cattolica who died during the 2011 Malaysian Grand Prix. Simoncelli had grown up in Coriano, immediately adjacent to the circuit. The new name was confirmed on 8 June 2012 at the San Marino round of the Superbike World Championship.