Diclofenac sodium is one of the non-steroidal anti-inflammatory drugs that is used as anti-inflammatory, analgesic, and antipyretic. N-acetyl cysteine is an antioxidant and free radical scavenger used to combat oxidative stress-induced damage in various tissues. Objectives: The current study was designed to investigate diclofenac sodium toxic effects upon the blood parameters, oxidative stress marker and spleen after repeated oral dose and evaluate the possible protective effect of N- acetyl cysteine when co-administered with it. Methods: Forty adult male albino rats were divided equally into four groups. Group I: the rats were fed on basal diet and distilled water. Group II received N-acetyl cysteine orally at the dose of 150 mg /kg /day. Group III: the rats were treated orally with diclofenac sodium at dose 5 mg /kg /day. Group IV received diclofenac sodium and N-acetyl cysteine at the same mentioned dose. After one month ,all animals were sacrificed and blood was collected for analysis. The spleen was preserved for histopathological examination. Results: The study proved that repeated oral administration of diclofenac sodium induced significant toxic effect on blood parameters, increased serum malondialdhyde level and histopathological changes in spleen. But these toxic effects declined markedly with N- acetyl cysteine co-administration. Conclusions: The present study concluded that diclofenac sodium has many toxic effects on blood parameters, induces oxidative stress and histopathological alteration in spleen tissues. Also, the study revealed that N- acetyl cysteine has a potential protective effect against such harmful effects.