Medication adherence is essential for managing chronic conditions, while non-adherence remains a widespread issue, leading to poorer health outcomes and higher healthcare costs. This study aimed to identify key adherence barriers, explore their relationship with patient satisfaction, and assess their impact on overall well-being among ambulatory patients in Albania. A cross-sectional study was conducted in three public urban health centers in Vlora, Albania, between November 2024 and January 2025. A total of 80 ambulatory patients were recruited using convenience sampling. Data were collected through face-to-face interviews using validated questionnaires, including the Adherence Barriers Questionnaire (ABQ), the Patient Satisfaction with Nursing Care Quality Questionnaire (PSNCQQ), and the Patient Health Questionnaire (PHQ-9) for depression screening. The study included 80 ambulatory patients (mean age 66.7 years; 48.7% female), predominantly diagnosed with diabetes (42.5%) and rheumatic diseases (36.3%). All participants reported at least one adherence barrier, with 92.5% experiencing multiple barriers. The most common were financial burden (91.3%) and fear of side effects (77.5%). A significant positive correlation was found between adherence barriers and depression severity (ρ = 0.518, < 0.0001), while patient satisfaction did not significantly influence adherence barriers (ρ = -0.217, = 0.053) or depression severity (ρ = -0.004, = 0.969). Multiple regression analysis showed that higher depression severity ( = 0.0049) was significantly associated with greater adherence barriers, while postgraduate education was associated with fewer barriers ( = 0.0175). Financial burden, fear of side effects, and psychological distress are key barriers to adherence among Albanian ambulatory patients. Although there are limitations inherent to the cross-sectional design and modest sample size, our findings highlight the potential benefit of routine mental health screening, targeted financial support, and improved patient education on medication management within primary care. These insights may help inform future research and interventions aimed at enhancing adherence and overall well-being. Patient satisfaction did not significantly impact adherence or depression. Targeted interventions focusing on financial support, mental health care, and patient education are needed to improve adherence and patient well-being. These findings underscore the need for integrated mental health and adherence support strategies within routine primary care services.