Increasingly, patient medication adherence data are being consolidated from claims databases and electronic health records (EHRs). Such databases offer an indirect avenue to gauge medication adherence in our data-rich healthcare milieu. The surge in data accessibility, coupled with the pressing need for its conversion to actionable insights, has spotlighted data mining, with machine learning (ML) emerging as a pivotal technique. Nonadherence poses heightened health risks and escalates medical costs. This paper elucidates the synergistic interaction between medical database mining for medication adherence and the role of ML in fostering knowledge discovery.We conducted a comprehensive review of EHR applications in the realm of medication adherence, leveraging ML techniques. We expounded on the evolution and structure of medical databases pertinent to medication adherence and harnessed both supervised and unsupervised ML paradigms to delve into adherence and its ramifications.Our study underscores the applications of medical databases and ML, encompassing both supervised and unsupervised learning, for medication adherence in clinical big data. Databases like SEER and NHANES, often underutilized due to their intricacies, have gained prominence. Employing ML to excavate patient medication logs from these databases facilitates adherence analysis. Such findings are pivotal for clinical decision-making, risk stratification, and scholarly pursuits, aiming to elevate healthcare quality.Advanced data mining in the era of big data has revolutionized medication adherence research, thereby enhancing patient care. Emphasizing bespoke interventions and research could herald transformative shifts in therapeutic modalities.© 2023 The Authors. Journal of Evidence-Based Medicine published by Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.