Background and Objective <p>Lenvatinib is a multi-kinase inhibitor approved as a first-line therapy for advanced hepatocellular carcinoma. In India and other low- and middle-income countries, immune checkpoint inhibitor-based regimens are not universally accessible, and real-world data on lenvatinib are limited. We evaluated the effectiveness, safety, and predictors of outcomes of first-line lenvatinib in Indian patients with advanced hepatocellular carcinoma.</p> Methods <p>This prospective observational cohort included consecutive patients with advanced hepatocellular carcinoma treated with first-line lenvatinib at the Regional Cancer Centre, Kerala, India, between March 2021 and May 2024. Lenvatinib was started at 8 or 12 mg once daily based on weight. Overall survival and progression-free survival were estimated using the Kaplan–Meier method. Cox regression analysis identified independent predictors of outcomes. Toxicities were graded using Common Terminology Criteria for Adverse Events Version 5.0.</p> Results <p>A total of 112 patients were enrolled; median age was 62 years, and 88% were male. The predominant etiologies were non-viral (83%), mainly non-alcoholic steatohepatitis and alcohol-related liver disease. Most patients (79 %) had Barcelona Clinic Liver Cancer stage C disease, with nearly half showing macroscopic portal vein invasion. At a median follow-up of 30.8 months, median overall survival was 13.3 months (95% confidence interval [CI] 10.6–16.6) and median progression-free survival was 8.1 months (95% CI 6.5–9.8). Multivariate analysis showed improved overall survival with non-viral etiology (hazard ratio [HR] 0.49, 95% CI 0.28–0.86, <i>p</i> = 0.014), radiological response (HR 0.40, 95% CI 0.22–0.71, <i>p</i> = 0.002), and subsequent therapy (HR 0.36, 95% CI 0.22–0.60, <i>p</i> &lt; 0.001), whereas portal vein invasion predicted worse overall survival (HR 1.67, 95% CI 1.06–2.61, <i>p</i> = 0.026). Grade ≥3 toxicities occurred in 38% of patients, mainly dermatologic, and no treatment-related deaths occurred.</p> Conclusions <p>Lenvatinib demonstrated favorable survival outcomes and manageable toxicity in advanced hepatocellular carcinoma in our cohort, with superior effectiveness in non-viral disease. Given some evidence suggesting that immune checkpoint inhibitors may be less effective in non-viral hepatocellular carcinoma, along with the high costs and lack of accessibility, lenvatinib could still be a viable first-line option for non-viral hepatocellular carcinoma in resource-constrained settings. This is even more relevant with the rising trend of non-viral related hepatocellular carcinoma in low- and middle-income countries.</p> Graphical Abstract <p></p>