Objective Liver function, tumor burden, inflammation level, and nutritional status are critical factors influencing tumor onset, progression, and metastasis. This study sought to investigate the prognostic significance and clinical relevance of biomarkers associated with these factors to develop a novel liver function-tumor burden-inflammation-nutrition (LTIN) score for patients with hepatocellular carcinoma (HCC) who received hepatectomy. Methods A retrospective analysis was conducted on 285 patients with HCC undergoing hepatectomy at two medical centers between July 2019 and July 2023. The patients were divided into a training set (n = 200) and a validation set (n = 85). The study evaluated the prognostic significance of eight relevant clinical indicators and developed an LTIN score using Least Absolute Shrinkage and Selection Operator (LASSO) regression. Kaplan-Meier survival curves and multivariate Cox regression analysis were utilized to determine the prognostic value of the LTIN score. Time-dependent receiver operating characteristic (ROC) analyses were used to compare the predictive performance of various prognostic factors. Results The LTIN score, derived from the albumin-bilirubin (ALBI) grade, tumor burden score (TBS), prognostic nutritional index (PNI), and prognostic inflammatory index (PII), effectively classified patients into high- and low-risk groups based on the optimal cut-off value. Patients with low-risk scores exhibited significantly better overall survival (OS) and recurrence-free survival (RFS) than those with high-risk groups in both the training and validation sets (P < 0.001). Furthermore, the LTIN score was identified as a significant independent prognostic factor for both OS (P < 0.001) and RFS (P < 0.001). The LTIN score also exhibited superior prognostic capabilities compared to the other indicators, Tumor-Node-Metastasis (TNM) staging system, and Barcelona Clinic Liver Cancer (BCLC) staging system. Conclusion Our findings indicated that the preoperative LTIN score has significant potential as a reliable predictor of OS and RFS for HCC patients underwent radical surgery. The LTIN score could further effectively guide treatment decisions and optimize follow-up strategies to enhance patients prognosis.