This cross-sectional study evaluated the performance of the Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) and the Fibrosis-4 (FIB-4) Index when they were used individually and in sequential combination to diagnose cirrhosis associated with hepatitis C virus infection. The final evaluation involved 906 people living with hepatitis C. The diagnostic performance of individual biomarkers at cut-off scores of 1.5 and 2.0 for the APRI and at 3.25 for the FIB-4 index was assessed. For the sequential combination method, the cirrhosis status of individuals with an APRI score between 1.0 and 1.5 were reassessed using the FIB-4. Transient elastography (TE) was used as the reference standard for diagnosing cirrhosis. The APRI, at a cut-off score of 1.5, showed a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 44.9%, 97.6%, 91.1% and 76.3%, respectively. Increasing the cut-off score to 2.0 produced a much lower sensitivity (29.6%) and NPV (71.9%). The FIB-4, at a cut-off score of 3.25, yielded a sensitivity, specificity, PPV and NPV of 40.8%, 97.3%, 89.1% and 75.0%, respectively. The sequential combination method demonstrated a much more optimal diagnostic performance (50.2% sensitivity, 96.6% specificity, 89.0% PPV and 77.9% NPV). Overall, the APRI and FIB-4 Index performed better in diagnosing cirrhosis associated with hepatitis C when they were used in sequential combination.