Background <p>Type 2 diabetes mellitus (T2DM) management relies significantly on medication adherence, yet non-adherence remains a prevalent issue affecting treatment outcomes. Understanding the factors contributing to non-adherence is crucial for developing effective interventions and improving patient care.</p> Aim <p>This study aimed to assess medication non-adherence among T2DM patients following up with health coaches in primary healthcare centers (PHCCs) in Makkah City and identify associated factors influencing adherence levels.</p> Methodology <p>A cross-sectional study was conducted among 327 T2DM adult patients. Data on socio-demographic characteristics, clinical, medication-related, and psychological factors, barriers to adherence, and communication difficulties were collected by health coaches at all 24 PHCCs in Makkah City using a structured interview questionnaire. Medication adherence was assessed using the Morisky, Green, and Levine Medication Adherence Scale-4 (MMAS-4), and participants were categorized into low, intermediate, and high adherence groups. Statistical analyses, including chi-square tests and logistic regression analyses with crude and adjusted odds ratios (OR), were performed to identify significant associations and predictors for non-adherence.</p> Results <p>A total of 327 participants were included. Of these, 50.8% were older than 50 years, 57.8% were female, 73.4% were married, 34.6% had university or postgraduate education, 84.4% were Saudi nationals, and 53.2% were unemployed. Good family support toward adherence to diabetes medications was reported by 76.1%. Smoking was reported by 15%, while 39.5% were overweight and 26.3% were obese. Additionally, 50.8% reported having other chronic diseases, and 28.1% reported diabetes-related complications. Regarding treatment, 69.4% were on oral antidiabetic therapy, 6.1% on insulin injections, and 24.5% on combination therapy. Moreover, 46.2% were taking medications for other chronic conditions. Depression was diagnosed in 11% of participants. Difficulties in managing diabetes and adhering to medications were reported by 26.4%, and 13.5% experienced side effects that affected adherence. Medication adherence levels were high in 48.3%, intermediate in 39.5%, and low in 12.2% of participants. Non-adherence was significantly associated with poor family support (<i>p</i> = 0.017), difficulty managing diabetes (<i>p</i> &lt; 0.001), and medication side effects (<i>p</i> = 0.001). In logistic regression analysis, poor family support (AOR = 1.83; 95% CI: 0.84–3.77, <i>p</i> = 0.023) and difficulty managing diabetes (AOR = 0.46; 95% CI: 0.18–1.49, <i>p</i> = 0.010) emerged as significant predictors of medication non-adherence.</p> Conclusion <p>This study highlights the multifactorial nature of medication non-adherence among patients with T2DM in primary healthcare settings. The findings demonstrate a complex interplay of psychosocial and clinical factors—particularly poor family support, difficulty coping with diabetes, and adverse medication side effects—that significantly impact adherence. These factors interact synergistically, amplifying the risk of non-adherence. Therefore, effective interventions should adopt a holistic, patient-centered approach that integrates family engagement, psychological support, and personalized medication management. Embedding these strategies within the health coach model may enhance adherence, optimize glycemic control, and reduce diabetes-related complications.</p>