B uffaloes (Bubalus bubalis) play an important part in many poor countries. They are used for agricultural economies, producing milk, meat, and draught force (Minervino et al., 2020). One of the greatest constraints in the exploitation of the production potential of buffaloes are its inherently lower reproductive efficiency, manifested by es-trus with low behavioral expression and/or not associated with ovulation, postponed sexual maturity, lower conception rates, and longer calving intervals (Baithalua et al., 2013).The corpus luteum (CL), a dynamic endocrine gland, controls the estrous cycle, embryonic development, implantation, and produce progesterone (P4), which is essential for research Article Abstract | It is fair to know how corpus luteum (CL) is a maestro of regulation of estrus cycle in Egyptian buffaloes. Hence, the study of molecular control of the CL in Egyptian buffaloes let us to know the mechanisms of this regulation. We aimed to (1) figure out the expression profile of apoptotic genes (TNF α -BAX -CASP3 -FASLG -AGTR2 -and NOS2) mRNAs during early, mid, and late stages of CL and (2) clarify the accompanied changes in progesterone (P4), nitric oxide (NO) concentrations and histological evaluation through different stages of CL in buffaloes. Forty five paired samples of ovarian tissue from buffaloes were obtained from slaughterhouse. Ovaries were collected and CLs were classified morphologically into three stages: early, mid and late stages. Moreover, the CLs were frozen at -80 °C for NO estimation in CLs homogenate, RNA isolation and gene expression. Blood samples were obtained for P4 serum levels estimation. Results showed a significant rise of TNF α mRNA during late stage of CL and increase the expression of CASP3, FASLG and AGTR2 mRNAs during mid-stage of CL. Furthermore, NOS2 mRNA was raised during early stage of CL. Surprisingly, NO in CL homogenate was raised through early and late stages of CL. Additionally, P4 increased in mid-stage of CL. Taken together, the fine tuning between apoptotic genes (TNF α -BAX -CASP3 -FASLG -AGTR2 -and NOS2) is required for proper functions of CL in Egyptian buffaloes. Thus, it might be concluded that expression pattern of apoptotic genes is changed according to the stage of CL.