Purpose: Patients with gastrointestinal tract cancer reported suboptimal adherence to oral anticancer agents, reducing the therapeutic benefit and increasing mortality risk. The Common-Sense Model of Self-Regulation highlights patients' perceptions of illness and treatment influence adherence. However, how these perceptions influence adherence remains unknown among this population. This study aimed to explore whether illness perceptions influence adherence via their effect on medication perceptions. Methods: A multi-center cross-sectional study design was conducted. Between July and August 2023, a questionnaire was administered to patients from four tertiary hospitals in Mainland China. Illness perceptions were assessed using the Brief Illness Perceptions Questionnaire. Medication perceptions were measured in medication belief and self-efficacy using the Belief about Medicines Questionnaire and Self-efficacy for Appropriate Medication Use Scale, respectively. Adherence was evaluated using the Morisky 4-item Medication Adherence Scale. Mediation analyses were conducted. Results: In total, 253 participants were recruited. Patients with worse negative illness perceptions reported higher concern, lower self-efficacy, and poorer adherence. Medication self-efficacy was positively associated with adherence, whereas the necessity and concern belief of taking oral anticancer agents were not. Illness perceptions, including the cognitive and emotional dimensions, had direct and indirect effects on adherence via its effects on medication self-efficacy. The indirect effect explained 26.63% of the total effect. Conclusions: The association between illness perceptions and adherence is partially mediated by medication selfefficacy. Strategies to foster positive illness perceptions may contribute to better medication self-efficacy and adherence. Attention should be equally focused on both the emotional and cognitive dimensions of illness perceptions.