This case report and comprehensive literature review highlights the significance of advanced molecular diagnostic techniques, particularly next-generation sequencing (NGS), in the identification and treatment of rare ALK fusion mutations in hepatocellular carcinoma (HCC). Through a detailed analysis of a single patient case, accompanied by a review of existing literature, we underscore the diagnostic challenges and therapeutic potential associated with rare ALK fusions in HCC. Our findings demonstrate the superior capability of NGS, both DNA-based and RNA-based, in detecting these mutations, leading to targeted treatment approaches with ALK inhibitors. The case report illustrates the practical application of precision oncology in HCC, showcasing significant clinical benefit and improved treatment outcomes with the use of ALK inhibitors for rare fusion types. This study not only contributes to the existing body of knowledge by documenting a rare instance of ALK fusion in HCC but also advocates for the integration of comprehensive molecular profiling into standard clinical practice to enhance personalized treatment strategies and patient care.