In the last decades, bio-plasticizers such as epoxidized soybean oil (ESBO) have emerged as eco-friendly alternatives to traditional phthalate plasticizers in poly(vinyl chloride) (PVC) compounds, owing to their non-toxic and stable properties. This study delves into the integration of ESBO as a bio-plasticizer and trimethylol propane trimethacrylate (TMPTMA) as a cross-linking agent in PVC irradiated by electron beam. Employing the melt-mixing method, varied concentrations of TMPTMA (1, 3 and 5 phr) along with ESBO or dioctyl phthalate (DOP) were incorporated into PVC, followed by electron beam irradiation at different doses (50, 100, 200 kGy) under ambient atmospheric conditions. A systematic approach, using a full factorial experimental design method, was adopted to evaluate the combined influence of TMPTMA concentration and irradiation dose on the physical and mechanical properties of PVC. The findings revealed a higher resistance to irradiation induced degradation as well as somewhat less thermal degradation in PVC samples with ESBO compared to those with DOP. While decreasing of the glass transition temperature (Tg) for bio-plasticized PVC was the same as that for PVC plasticized by DOP, bio-plasticized PVC samples showed higher tensile strength and thermal dimensional stability and less plasticizer migration. A detailed analysis of hot-set test outcomes and tensile mechanical properties, facilitated by the experimental design methodology, highlighted that the irradiation dose had a more profound impact on the properties of PVC than the TMPTMA concentration. The study also identified an interaction effect between these variables, and their influences on the tensile strength and hot-set were modeled.