Diclofenac sodium is normally used as anti-inflammatory and pain killer drug. The current study was performed to examine the possible protective roles of the date palm pollen and silymarin against diclofenac sodium (DS)-induced histopathological changes in the spleen of rats. Rats were divided into nine groups. Group1 (control), group2 (DS group) was administrated 15 mg/kg b.wt. of DS, group 3 (Date Palm Pollen ,DPP group; 100 mg/kg b.wt),group 4 (silymarin, Sil. group; 100 mg/kg b.wt), group 5 (DPP+DS group), group 6 (DS+DPP group),group 7 (Sil. +DS group), group 8 (DS+ Sil. group) and group 9 (DPP combined with SIL +DS group). DS resulted in a significant alterations in the splenic architecture indicated by cell necrosis at the white pulp, lymphocytic cell necrosis at the red pulp and depletion of lymphocytes at the white and red pulps. Each date palm pollen and silymarin restored the normal histological structure of the spleen. Also, the administration of the combined date palm pollen and silymarin before diclofenac sodium protected the spleen structure against the toxicity of diclofenac sodium. So, the data from this study suggested that date palm pollen and silymarin (as antioxidants) prevented DS-induced spleen structure toxicity and may be beneficial in protecting the therapeutic index of DS.