Limited evidence is available on the impact of direct-acting antiviral (DAA) therapy on immune activation biomarkers in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). This study aimed to characterize longitudinal changes in soluble intercellular adhesion molecule-1 (sICAM-1), soluble β2-microglobulin (sβ2M), and soluble CD14 (sCD14), following DAA treatment in an HIV/HCV-coinfected cohort in Indonesia. A prospective study was conducted involving 132 HIV/HCV-coinfected individuals treated with sofosbuvir/daclatasvir for 12 or 24 weeks. Plasma samples were collected at baseline and 12 weeks post-DAA therapy. Levels of sICAM-1, sβ2M, and sCD14 were quantified using enzyme-linked immunosorbent assay (ELISA). Linear regression analyses were performed to identify predictors of biomarker changes. A sustained virological response was achieved in 96.2% of coinfected participants. At baseline, the HIV/HCV-coinfected group exhibited significantly higher levels of sICAM-1 and sCD14 compared to levels found in HIV monoinfection. At 12 weeks post-treatment, significant reductions in sICAM-1 (p < 0.0002) and sβ2M levels (p < 0.0002) were observed, irrespective of the baseline liver fibrosis stage. No significant change was noted in sCD14 levels. Notably, sICAM-1 levels post-treatment remained elevated compared to those in HIV monoinfection. Lower baseline serum albumin was an independent predictor of sβ2M reduction. DAA therapy was associated with significant reductions in sICAM-1 and sβ2M levels among HIV/HCV-coinfected individuals, irrespective of liver fibrosis stage. These findings highlight the immunomodulatory benefits of DAA therapy across different stages of liver disease in the Indonesian population. © 2025 Wiley Periodicals LLC.