The COVID-19 pandemic's first wave and subsequent lockdowns disrupted global healthcare systems, significantly impacting essential services including tuberculosis (TB) care. Non-adherence to anti-TB drugs is a critical concern, leading to treatment failure, drug resistance, and increased morbidity and mortality. This study assessed the rate and determinants of non-adherence to TB treatment among patients at TB centers during the first wave of the pandemic. A cross-sectional study was conducted from June 15 to July 30, 2020, involving 255 TB patients at three centers in Mogadishu. Data were gathered using the Morisky Medication Adherence Scale-8 (MMAS-8) through structured interviews and analyzed using descriptive statistics and binary logistic regression. The study found a 34.5% non-adherence rate during the pandemic. Key reasons for non-adherence included forgetting to take medication (33%), feeling well (29%), experiencing side effects (18%), and fear of contracting COVID-19 (16%). Significant factors associated with non-adherence were age groups 25-34 years (OR = 2.96, p = 0.024) and 35-44 years (OR = 4.55, p = 0.005), unemployment (OR = 2.57, p = 0.037), smoking (OR = 3.49, p = 0.029), tobacco use (OR = 4.15, p = 0.034), proximity to a health facility (OR = 0.44, p = 0.033), perception of healthcare providers as very friendly (OR = 0.24, p = 0.031) or friendly (OR = 0.45, p = 0.023), being in the continuous treatment phase (OR = 3.2, p < 0.001), and experiencing adverse treatment effects (OR = 2.42, p = 0.003). Non-adherence to anti-tuberculosis treatment was notably high in Mogadishu during the first wave of the pandemic, necessitating targeted interventions to improve adherence.