Chronic hepatitis C virus (HCV) infection remains a major global health burden, potentially leading to cirrhosis and hepatocellular carcinoma. Direct-acting antivirals (DAAs) have improved treatment outcomes, achieving high sustained virologic response (SVR) rates. However, real-world evidence from Mexico remains limited. This study aimed to evaluate DAA effectiveness in Mexican patients with chronic HCV infection and compare outcomes according to cirrhosis status. A retrospective, multicenter cohort study was conducted across five public healthcare institutions in Mexico. We included 253 patients who received DAA therapy. The primary outcome was SVR, defined as undetectable HCV RNA after treatment. Clinical, demographic, and treatment-related variables were analyzed, with statistical significance set at p < 0.05. Overall, SVR was achieved in 94.5% of patients. Among those with cirrhosis (54.1%), the SVR rate was 95.6%, compared with 93.1% among those without cirrhosis (p = 0.536). Patients with cirrhosis were older and had longer treatment durations, while baseline viral load and genotype distribution were comparable. Treatment completion was high (94.1%), with low discontinuation rates and no significant differences by cirrhosis status. DAAs were highly effective in Mexican patients with chronic HCV infection, regardless of cirrhosis status. Expanding access to diagnosis and treatment is essential to reduce disease burden and achieve hepatitis C elimination goals.