Abstract Background and Aim Patients living with diabetes mellitus have a high burden of psychological distress such as depression and anxiety as well as impaired quality of life, which may negatively impact their adherence to medications, glucose control, and health‐related costs. This study assessed the impact of quality of life and depression on medication adherence among patients with type 2 diabetes (type 2 diabetes mellitus [T2DM]) in a tertiary care setting in Ghana Methods The study was a cross‐sectional study involving 238 patients with diabetes aged 18 years and above. Validated tools were used to assess medication adherence, depressive symptoms, and quality of life. Structural Equation Modeling was adopted to examine the mediation effect of quality of life on the relationship between depression and medication adherence among participants. Results The mean age of the participants was 58.82 ± 13.49, and 169 (71.0%) out of a total of 238 respondents were females. Depression had a significant direct relationship with the quality of life of respondents [aβ (95% confidence interval, CI) = −0.20 (−0.03, −0.00), p