Background and aim: Inflammatory biomarkers are commonly utilized and remain a topic of ongoing discussion regarding their role in predicting outcomes in advanced hepatocellular carcinoma (HCC). The overall survival (OS) of patients with advanced HCC who received first-line systemic therapy at a tertiary care hospital in Pakistan was examined in this study in relation to the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline and 1 month after treatment. Materials and methods: The study tracked 107 patients with advanced HCC from 2017 to 2024 who received atezolizumab/bevacizumab, lenvatinib, and sorafenib as therapy. Pretreatment and posttreatment (1 month) NLR and PLR values were analyzed. The most appropriate NLR and PLR cutoff thresholds were determined using receiver operating characteristic (ROC) analysis. Kaplan-Meier survival curves and log-rank tests were used to determine OS. Results: Nine months was the median OS, with a 95% confidence interval (CI) ranging from 5 to 13.7 months. Patients with a pretreatment NLR below 2.72 had a median survival of 13 months (95% CI: 9–32 months), whereas those with an NLR of 2.72 or higher had a median survival of 5 months (95% CI: 4–11). Similarly, patients with a pretreatment PLR under 102.86 achieved a median survival of 13 months (95% CI: 9–32), while those with a PLR equal to or above 102.86 experienced a median survival of 5 months (95% CI: 4–14). Treatment-related side effects, including deranged liver function tests, led to dose adjustments in 83.9% of patients and significantly influenced survival outcomes. Conclusions: Higher pretreatment NLR and PLR were related with lower survival outcomes in advanced HCC patients undergoing first-line systemic treatment. Although not statistically significant, these biomarkers show potential as predictive tools when integrated with established systems like Albumin-Bilirubin grading and Child-Pugh classification. Additional studies are required to validate their significance, particularly in the context of emerging therapies. Clinical significance: The NLR and PLR, combined with established tools, offer a cost-effective approach to refine patient selection and improve outcomes in advanced HCC, particularly in resource-limited settings.