Cancer is a complicated disorder with negative impacts on humans' lives that intensifies the mortality rate. Chemotherapy and/or radiotherapy (RT) are used for cancer treatment to achieve the most efficient management of cancer. Cyclophosphamide (CP) is a recommended medication for plentiful tumors. It has valuable anti-neoplastic and immunosuppressive impacts. The combination of CP and gamma radiation (R) can boost the curative benefits of some malignant diseases. However, this combination has some drawbacks, such as testicular damage. Korean red ginseng (Panax ginseng; KRG) is rich in ginsenoside phytochemicals that exhibit antioxidant and anti-inflammatory activities. The purpose of the current investigation was to determine whether orally administering KRG water extract might significantly protect against CP and/or R toxicities. KRG exhibited significant amelioration of the testicular architecture as well as sperm count and sperm motility; and restored the serum levels of male reproductive hormones, TH, FSH, and LH. Moreover, it improved the levels of LDH, ACP, Ca2+, MDA, NO, H2O2, and GSH. Also, it boosted the SOD, CAT, and GPX activities, lowered the elevated levels of TNF-α, IL-6, NF-κB, IFN-γ, and PD-L1, down-regulated the protein expression ratios of p38-MAPK) and EGFR, and regulated the gene expression ratios of AR, iNOS, p65 NF-κB, miR-18a, and let7e in the testis tissues of R, CP, and R/CP intoxicated groups. It could be concluded that KRG may improve testicular impairment by attenuating oxidative stress and inflammatory responses via the regulation of PD-L1 and IFN-γ levels, miR-18a and let7e genes' expression, and p38-MAPK and EGFR proteins' expression.