Several studies have highlighted the potential of pyroptosis as a target for cancer treatment. This article focuses on the specific roles and clinical implications of pyroptosis-related genes (PRGs) in soft tissue sarcoma (STS). By analyzing differentially expressed PRGs in STS compared to normal tissue, our study evaluates the interactions, biological functions, and prognostic values of PRGs in STS. Through LASSO COX regression analysis, a five-gene survival related-risk score (PLCG1, PYCARD, CASP8, NOD1, and NOD2) was created, which examined both in TCGA cohort and training cohort (GSE21050, GSE30929, and GSE63157). Furthermore, we developed a nomogram incorporating clinic factors and the risk scores of the PRGs, which showed decent accuracy of prediction as evidenced by calibration curves. Additionally, our study analyzed the Tumor Immune Dysfunction and Exclusion Algorithm (TIDE) and IMvigor 210 cohorts to investigate the immunotherapy response, and found that immunotherapy was more beneficial for patients with minimal risk of PRGs than those exhibiting greater risk. Finally, GDSC and CAMP databases were used to screen for effective chemotherapy or targeted drugs that are sensitive to the high-risk populations, including doxorubicin, imatinib, and sorafenib. In conclusion, this study provides a comprehensive analysis of the PRG landscape in STS and constructs a novel risk model to predict prognosis and different therapeutic responses of STS patients, which is helpful for achieving precision medicine.