In this study, the induced defects and modifications enhanced by alpha particle on CdO and ZnSe-doped polymethyl methacrylate (PMMA) were investigated. Casting method was used to prepare three sets of thin polymeric sheets doped with variable concentrations of the selected fillers. The prepared CdO and ZnSe particles were in the range 3–21 nm. The samples were irradiated with 4.5 MeV α-particle emitted from 241Am radioactive source at gradually increased fluence. The enhanced change that occurred in the physical properties for both types of samples due to α-particle irradiation was measured using Fourier transform infrared (FTIR), X-ray diffraction (XRD), ultraviolet–visible spectroscopy (UV–Vis), photoluminescence (PL) spectroscopy. All the pristine samples exhibited two separated direct band gaps around 4.0 eV and 4.6 eV, while the irradiated samples showed decreasing for the first band gap up to 3.71 and the second gap remained almost unchanged. The three investigated sets displayed PL emission peaks within the range 270–700 nm. The intensity of the PL peaks was increased by increasing the filler concentration. The net PL was quantified using the area under the emission peaks which showed that α-particle causes interchangeable defects and cross-linking processes. The formation of C–H and O–H function groups due to α-particle interactions was confirmed by FTIR analysis. The results revealed that the filler–polymer interface has a great impact on the formed defects which control the observed characteristics in the polymeric composite medium. The presented data are very helpful for α-particle dosimetric applications using these types of polymeric composites.