Our study helps to evaluate the immune response, antioxidative status, and resistance against heat stress (HS) in Clarias gariepinus treated with propolis extraction; the results will contribute to theories of fish physiology and immunity under high-temperature conditions. Forty-five fish were divided into three equal groups: the control, the HS group at 36 °C, and the HS treated with alcoholic extraction of propolis that dissolved in water for 3 weeks. The results of our study suggested that the stress response differs among tissues thymus, spleen, and liver. All the tissues showed alteration in morphological and cytological structure at the light microscope (LM) and transmission electron microscope (TEM); thymus showed edema and thymocyte destruction; the spleen detected collagen deposition, and the liver displayed endoplasmic reticulum amplification (ER). In addition, we examined oxidative stress and antioxidant