Cyclophosphamide (CTX) is an effective anticancer therapy. It is known to cause oxidative stress and cytotoxic effects, especially on the immune system. Pentoxifylline and Nigella sativa seeds both possess antioxidant and anti-inflammatory properties. This study explores the ameliorative impact of both pentoxifylline and nigella sativa over the splenic damage induced by cyclophosphamide. Thirty-six adult male albino rats were separated into six groups from six each and received treatment for 10 days. Group I (control) received saline 0.9% solution orally via intragastric tube, group II received pentoxifylline (150 mg/kg) orally, group III received nigella sativa oil (20 mg/day) orally, group IV received a single intraperitoneal injection (IP) of CTX (200 mg/kg), group V received pentoxifylline (150 mg/day) orally for 10 days and at the 8th-day animals received single IP injection of CTX (200 mg/kg), group VI received nigella sativa oil (20 mg/day) orally for 10 days and similarly at the 8th-day animals received single IP injection of CTX (200 mg/kg). Light microscopic and ultrastructure changes in the spleen of the different experimental groups were examined. CTX induced splenic damage in the form of a disrupted and detached capsule of the spleen, lymphocyte loss with marked thickening and dilatation of the central artery in the white pulp, and cellular loss and congested blood sinusoids in the red pulp. The use of pentoxifylline and nigella sativa resulted in the restoration of splenic tissue. Pentoxifylline showed a more protective effect than nigella sativa on the splenic tissue against CTX-induced damage.