The study aimed to analyze and compare dosimetric differences with various thicknesses and frequencies of bolus in post-mastectomy intensity-modulated radiotherapy. Based on the Oncentra4.1 treatment planning system, Thirty-eight post-mastectomy patients were selected randomly between 2017 and 2021. Three sets of simulated treatment planning with 5_mm all, 5_mm half, and 10_mm half virtual boluses were formed. A total prescribed dose of 50 Gy regimen was delivered in 25 fractions over 5 weeks, in which half-time bolus was used for 15 out of 25 fractions. The dosimetric parameters of target areas, skin, and organs at risk were compared. Furthermore, normal tissue complication probability (NTCP) was evaluated for the skin. Regarding the D₂, D₅₀, V₉₀, V₉₅, and V₁₁₅ of the clinical target volume, the 5_mm all bolus group was prominently better than other groups, and the D₅₀ and V₉₀ of the clinical target volumes were statistically significant (p < 0.05). Regarding the D₂, D₅₀, D₉₅, D₉₈, D_max, V₉₀, V₉₅, V₁₁₅, homogeneity index (HI), and conformity index of the planning target volume, the 5_mm thick bolus group was prominently better than other groups, and the D₅₀, D₉₅, D₉₈, V₉₀, V₉₅, and HI of the clinical target volumes were statistically significant (p < 0.05). For organs at risk, there was no statistical significance for the three planning groups, but the 5_mm all bolus group was prominently better than other groups in the V₄₅ of the esophagus, V₃₀, V₄₀, and D_max of the heart, V₅₀, D_max, and D_mean of the humerus head, V₂₀, V₃₀, and D_max of the left lung, D_max and D_mean of the thyroid, and D_mean of the trachea. Calculated with the 5_mm all bolus, the mean dose, V₄₀, V₄₅, and V₅₀ for the skin structure, were all higher than other bolus regimens, while the dose maxima (Skin_max and V₅₅) were all lower than others. Regarding the skin radiobiological evaluation, the NTCP of the 5_mm all bolus group was prominently better than other groups and was statistically significant (p < 0.05). Besides, the monitor unit of 5_mm all bolus regimen was the minimum compared with other groups and was statistically significant (p < 0.05). Therefore, the 5_mm all bolus group can not only improve the dose but also reduce the hot dose of skin and target volume, as well as reduce the NTCP. Our study provides a clinical reference in the delivery of post-mastectomy radiotherapy.