Background: Mongolia, as a country with a high burden of liver disease caused by viral infections, has prioritized reducing the spread of viral hepatitis and sexually transmitted infections (STIs) in line with the WHO strategy for 2022–2030. Orders A/133 (2023) and A/18 (2024) issued by the Ministry of Health mandate that healthcare providers initiate screening of hospitalized patients for hepatitis B and C viruses, syphilis, and HIV infection. Among infectious diseases registered in Mongolia, STIs rank among the leading causes, with more than 40% of reported cases being newly diagnosed syphilis. Hepatitis C virus (HCV) infection and syphilis are transmitted via the parenteral route, can lead to chronic disease, and co-infection represents a serious condition that accelerates liver damage and negatively affects treatment outcomes. Syphilis infection places additional stress on liver function and exacerbates HCV-related inflammation. Aim: This study aimed to investigate how syphilis co-infection affects the biochemical and clinical course of acute hepatitis C virus infection. Materials and Methods: A retrospective, hospital-based cross-sectional study design was used. A total of 74 patients diagnosed with acute hepatitis C virus infection and treated at the National Center for Communicable Diseases between 2025 and 2026 were randomly selected. Data were collected from medical records. Patients were divided into two groups based on syphilis serology results: HCV mono-infection and HCV with syphilis co-infection. Differences between variables in the two groups were analyzed using the T-test, with statistical analysis performed using SPSS version 26. A p-value <0.05 was considered statistically significant. Results: Of the study participants, 17 (23%) had syphilis co-infection. There were no statistically significant differences in age and sex between the groups (p=0.982). In the co-infected group, 23.5% had high RPR titers (indicative of active/new infection). Clinically, general signs of infection and intoxication (35.3%), fatigue (100%), dyspeptic syndrome (100%), and intoxication syndrome (100%) were predominant. Biochemical analysis showed significantly higher levels in the co-infected group compared to the mono-infected group: total bilirubin (192.4 vs 110.5 μmol/L, p<0.01), alkaline phosphatase (245.8 vs 132.1 U/L, p=0.004), and ALT (1240.5 vs 850.2 U/L, p=0.03). Kaplan–Meier analysis demonstrated that the mean time for ALT normalization was longer in the co-infected group (26.4 days) compared to the mono-infected group (20.7 days) (p=0.006), indicating prolonged recovery. Conclusion Syphilis co-infection worsens the clinical course of acute hepatitis C, deepens jaundice and cholestatic syndrome, and prolongs the normalization of biochemical parameters.