Background: Early detection of hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD) is critical for improving prognosis. Traditional biomarkers like alpha-fetoprotein (AFP) have limited sensitivity, prompting the need for alternative non-invasive biomarkers. This study evaluates the diagnostic accuracy of des-γ carboxy prothrombin (DCP), glypican-3 (GPC3), miR-122, miR-21, and circulating tumor DNA (ctDNA) for early HCC detection. Methods: A total of 120 CLD patients, including 20 with HCC, were recruited from Ziauddin University Hospital, Karachi, between June 2023 and February 2024. Biomarker levels were measured and compared between HCC and non-HCC groups. Receiver operating characteristic (ROC) curves were used to assess diagnostic performance, and multivariate combinations of biomarkers were analyzed to enhance diagnostic accuracy. Results: DCP and ctDNA outperformed AFP, with AUCs of 0.91 and 0.93, respectively, compared to 0.82 for AFP. GPC3 and miR-122 also demonstrated high diagnostic accuracy, with AUCs of 0.88 and 0.87. Combining AFP, DCP, and miR-122 improved the AUC to 0.95, while adding ctDNA increased the AUC to 0.97, with 93% sensitivity and 94% specificity. Conclusion: Non-invasive biomarkers such as DCP, GPC3, miR-122, and ctDNA significantly enhance early detection of HCC in CLD patients compared to AFP alone. Combining these biomarkers offers a promising approach for improving diagnostic accuracy, especially in early-stage HCC. Further validation in larger, diverse cohorts is warranted to establish their clinical utility.