This study aimed to introduce new composites, containing polyamide-6 (PA6) and lead monoxide (PbO), to protect against ionizing photon sources used for diagnostic and therapeutic purposes. Five composites, containing various weight percentages of PbO filler (0, 5, 10, 20, and 50%), were developed in this study. Initially, the numerical attenuation value was estimated using the XMuDat program by calculating the mass attenuation coefficients at different energy levels. Next, the samples were synthesized based on the melt-mixing method in a laboratory mixing extruder. Their characteristics were also determined by scanning electron microscopy (SEM), energy dispersive X-ray (EDX) analysis, X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Finally, experimental radiation attenuation tests were carried out. Based on the SEM results, the acceptable filler weight percentage was up to 20%. However, substantial aggregates were formed at the highest weight percentage. The results of XRD analysis showed a higher tendency for crystallization by decreasing the amorphous area while increasing the filler weight percentage. Moreover, the mass loss rate was monitored at different temperatures, revealing that the filler incorporation improved the thermal durability of the samples. The radiation results showed a good agreement between the experimental and computational data, except when aggregates formation was substantial. The experimental data revealed that when the lead weight percentage increased from 0% (crude PA6) to 50%, the half-value layer decreased from 3.13 to 0.17 cm at an energy level of 59 keV and from 7.28 to 4.97 cm at an energy level of 662 keV. Following the studied mechanism, the superiority of lead/polyamide composites can be found in the high adsorption of photon radiation at low energies (E < 0.20 MeV) and significant attenuation at medium and higher energies. Considering these promising results, the shielding properties of these composites can be further analyzed via more practical investigations.