<p>Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sorafenib is the first FDA-approved systemic therapy for advanced HCC. This study investigates the influence of IL-23R (rs7517847) and ATG-10 (rs10514231) genetic polymorphisms on Sorafenib response, survival outcomes, average tolerable dose, and adverse events. This prospective open-label cohort study included 100 HCC patients, assessing IL-23R and ATG-10 genotypes via real-time polymerase chain reaction (RT-PCR). Patient's responses were evaluated using modified RECIST criteria. Statistical analyses evaluated the association of genetic variants with response, progression-free survival (PFS), overall survival (OS), average tolerable Sorafenib dose, and adverse events. IL-23R TT carriers had the highest Sorafenib response rate (80%) compared to GT (13.3%) and GG (6.7%) (<i>P</i> = 0.021), while ATG-10 TT carriers had a 13.9-fold increased response likelihood (<i>P</i> = 0.001). The T allele in ATG-10 significantly predicted longer PFS (<i>P</i> = 0.025) and OS (<i>P</i> = 0.011), suggesting a potential prognostic role. IL-23R GG carriers received significantly higher Sorafenib doses than TT (<i>P</i> = 0.0174) and GT (<i>P</i> = 0.0227), whereas ATG-10 had no effect on dosage. However, its CT genotype was significantly associated with a higher risk of Hand–Foot Syndrome (<i>P</i> = 0.012), and independent of dose (<i>P</i> = 0.0018). IL-23R and ATG-10 polymorphisms influence Sorafenib response, survival, and tolerability in HCC patients. Genetic screening may improve personalized treatment strategies by optimizing Sorafenib efficacy and minimizing toxicity.</p><p>This trial was registered on clinicaltrials.gov with registration number NCT06030895, registered on “September 11th, 2023,” retrospectively.</p>