Background. Global tuberculosis (TB) disease deaths rise comparable to the one seen in 2015 (by 200,000) or even in 2012 (by 400,000) as a result of the potential impact of the COVID-19 pandemic. Ethiopia’s Gambella region is leading for years in terms of TB cases and its comorbidities. The TB control program effectiveness depends on in large on the patients completing the appropriate treatment regimen. Hence, the objective of this study was to determine the determinants of nonadherence to anti-TB drug treatment among patients in Gambella regional state of Ethiopia. Methods. A case-control study was conducted on cohorts of TB patients sampled from four public health facilities in Gambella Region from January 2019 to 2020, followed by 18 months of follow-up. The total sample size was 296 patients (74 cases and 222 controls) with a response rate of 97.3% (288 : 72 nonadhered cases and 216 controls). Cases (nonadhered) were TB patients who missed 10% of the doses while controls were patients, who completed 90% or more doses. Results. TB patients, who perceived stigma [AOR = 2.7 at 95% CI (1.1–6.6) with
P
value <0.05], failed to receive any counseling during the treatment course [AOR = 65.24 at 95% CI (11.69–363.95) with
P
value <0.01], patients who used to smoking during treatment [AOR = 15.4 at 95% CI (7.7–30) with
P
value <0.01], taking TB medications regularly has no benefits [AOR = 6.8 at 95% CI (1.8–24.9) with
P
value <0.05], and patients believing TB disease as not severe [AOR = 8.38 at 95% CI (2.0–34.6) with
P
value <0.05] were significantly or highly significantly associated with nonadherence to anti-TB drugs medications. Conclusion. The determinants of nonadherence to anti-TB treatment among TB patients in the Gambella region during the study period were the absence of counselling services, and patients’ behavior (smoking habits, undermining the severity of TB disease, lack of trust in the outcomes of regular medications, and perceived stigmatization). Accordingly, capacitating healthcare providers and workers at all TB clinics for effective counseling , preventing perceived stigma by protecting the patient’s secrecy, and routine health education has paramount importance for effective TB control in Gambella.