Despite the various theoretical frameworks of acculturation, the mechanisms by which acculturation affects health and well-being remain unclear. This cross-sectional study explores the role of acculturation in self-rated health (SRH) among international medical students. The study was conducted in 2024 at the Medical University – Sofia and included 326 participants. The Stephenson Multigroup Acculturation Scale (SMAS) was employed to assess cultural influences from both the host and home countries, focusing on two dimensions: Ethnic Society Immersion (ESI) and Dominant Society Immersion (DSI). SRH was measured using a five-category Likert scale. Covariates included perceived stress, social support, and health behaviour factors. Logistic binary regression was applied for analysis. The findings revealed that most international medical students rated their health as good (56.4%). Poor health was significantly associated (p < 0.05) with lower ESI (Mdn = 3.4), higher stress levels (Mdn = 22), and a lack (31.9%) or insufficiency (54.2%) of physical activity (PA). ESI emerged as a significant predictor of good health (Exp(B) = 0.403; p = 0.004). The impact of DSI on poor SRH was mediated by PA (Exp(B) = 4.629 and Exp(B) = 2.699, p < 0.05 for both risk groups). The results of this study can be useful in planning health and social services for international students, considering their specific needs.