The Mediterranean diet (MD) is associated with many health benefits. The association between the MD and food neophobia (FN) is still unexplored in adults. The present cross-sectional study was aimed to explore the relationships between adherence to the MD, FN, and sociodemographic variables in a large Italian cohort. Familiarity and frequency use (FFI) of prototypical and non-prototypical Mediterranean foods were used to calculate a new adherence index: the Italian Taste Mediterranean Index (ITMI). The FFI of all Mediterranean foods increased with age, while butter, soft drinks, red/cured meat, and sweets were more common in younger people. Accordingly, ITMI increased with age (F_2,2384 = 54.11; p < 0.0001). Women recorded a higher ITMI (6.70) than men (6.10). Individuals with high FN showed higher FFI for soft drinks and sweets and lower ones for most typical MD foods, than individuals with low FNs. A decrease of ITMI was recorded with the increase of the FN(F_2,2384 = 22.84; p < 0.0001). With ageing, ITMI increased even in individuals with a high FN. The results suggest that FN may negatively affect adherence to the MD, lowering its potential health benefits, in the adult population. Monitoring of food habits, dietary education, and anxiety management, may be valuable tools to control FN and support the adherence to the MD.