The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is widely used to assess patient status but relies on subjective judgment and may not fully reflect their physical reserve. While studies have shown that skeletal muscle quality and quantity are associated with patient prognosis, their role in cancers of unknown primary (CUP) remains unclear. Therefore, this study aimed to investigate whether computed tomography (CT)-based skeletal muscle indicators reflect physical reserve and their prognostic value in patients with CUP. This study enrolled 184 patients with CUP, comprising both inpatients and outpatients, who were diagnosed at Seoul St. Mary's Hospital between 1 January 2008, and 30 June 2024. Overall survival (OS) was evaluated using the Kaplan-Meier method and analyzed using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazard models. Statistical significance was defined as < 0.05. Correlation analyses were conducted to evaluate the relationships between skeletal muscle density (SMD), skeletal muscle index (SMI), and other prognostic factors. SMD was positively correlated with SMI and negatively correlated with age, neutrophil-to-lymphocyte ratio, Charlson Comorbidity Index (CCI), and ECOG-PS. Jonckheere's trend test revealed that SMD decreased significantly as CCI and ECOG-PS increased ( < 0.001), indicating that a higher comorbidity burden and poorer performance status were associated with lower SMD. Both ECOG-PS and SMD were identified as prognostic factors in the univariate analysis of survival; however, only SMD demonstrated statistical significance regarding prognostic value in the multivariate analysis ( = 0.004) SMD, as a measure of muscle quality, demonstrates superior prognostic value compared to the subjective ECOG-PS and may serve as a reliable objective tool for assessing physical reserve in patients with CUP.