Background: Adherence to epilepsy treatment varies greatly and is often compromised by adverse drug reactions. Spontaneous reporting of these reactions has improved pharmacovigilance in many countries. Knowledge, attitudes, and behavior are also key factors influencing treatment adherence. This study aimed to investigate the types of adverse drug reactions in epilepsy, as well as the knowledge, attitudes, and behavior of patients, and how these factors relate to medication adherence. Methods: This cross-sectional study assessed adverse drug reactions using the Indonesian version of the Liverpool Adverse Event Profile and medication adherence with the Morisky Adherence Questionnaire. Knowledge, attitude and behavior were measured using a self-reported Indonesian knowledge-attitude-behavior questionnaire. Data were collected at two periods of time (2019 and 2022), in which the first period measured adherence, and adverse drug reactions, while the second period measured adherence, and adverse drug reactions, alongside knowledge, attitude, and behavior. Data were gathered from epilepsy patients at the neurology outpatient clinic at Cipto Mangunkusumo National Referral Hospital, and analyzed using Chi-square, likelihood ratio, independent t-test, or Mann–Whitney U Tests, followed by multivariate logistic regression. Results: Adherence rates in both periods exceeded 50% (50.88% vs. 55.70%). Adverse drug reactions were reported by 78.07% of subjects, and were significantly associated with non-adherence (P = 0.007). The mean knowledge score was 15.41 ± 3.83, and lower knowledge scores were linked to higher odds of non-adherence. Although not statistically significant (P = 0.077), higher knowledge scores showed a trend toward more frequent reporting of adverse drug reactions. Female subjects had higher odds of adherence compared to males (P = 0.013). Conclusions: Our findings suggest that adverse drug reaction reporting, along with patient knowledge, attitudes, and behavior, are important factors associated with medication adherence. Targeted interventions by healthcare providers to support these areas may help improve adherence in people with epilepsy. © The Author(s) 2026.