Background: Poor medication adherence is a serious barrier to successful chronic disease management. Previous reviews reported that low health literacy could be associated with medication non-adherence but conclusions were uncertain. Aim: The aim of this systematic review was to clarify the relationship between health literacy and medication adherence in adults with chronic diseases. A secondary objective was to identify the factors that influence medication adherence. Method: Publications analyzing the relationship between health literacy and adherence in adults with chronic diseases were identified through 6 databases between 2015 and 2020. A quality assessment was conducted in order to improve the interpretation of the relationship between health literacy and medication adherence. A narrative synthesis was then performed to describe the relationship between health literacy and medication adherence. The factors influencing medication adherence were then analyzed as a secondary outcome. Results: Among the 27 studies, 17 and 10 were considered to be of good and medium methodological quality, respectively. Concerning the relationship between health literacy and adherence, 14 reported a positive relationship, 1 study suggested a negative relationship, 3 found mixed results, and 9 reported not finding a relationship. Patient-related factors such as medication beliefs, self-efficacy, or medication knowledge, as well as demographic factors such as ethnic minority and incomes influence medication adherence. Conclusion: The present review confirms an unclear relationship between health literacy and medication adherence. Although health literacy plays a substantial role in medication adherence, other factors must be taken into account when addressing non-adherence.