Background <p>Cisplatin (CIS) is an effective chemotherapeutic agent; however, its clinical use is limited by serious adverse effects, including testicular toxicity, which is primarily mediated by oxidative stress, inflammation, and cell death pathways. Diacerein (DIA), a slow-acting anti-inflammatory drug, has recently gained attention for its antioxidant and cytoprotective properties.</p> Methods <p>Twenty-four adult male albino rats were randomly allocated into experimental groups and treated with DIA (50&#xa0;mg/kg, orally) for 14 consecutive days, along with a single intraperitoneal injection of CIS (7&#xa0;mg/kg) on day 8. At the end of the experimental period, rats were humanely euthanized. Testicular tissues and serum samples were collected for histopathological and biochemical analyses.</p> Results <p>DIA markedly attenuated CIS-induced testicular damage, as evidenced by improved histological architecture, increased testicular weight, and restored serum testosterone levels. It alleviated oxidative stress by reducing malondialdehyde (MDA) levels and enhancing antioxidant defenses, including superoxide dismutase (SOD), glutathione (GSH), Nrf2, and HO-1 expression. Furthermore, DIA suppressed inflammation via downregulation of NF-κB and pro-inflammatory cytokines (TNF-α and IL-1β). In addition, DIA inhibited CIS-induced pyroptosis by reducing the expression of NLRP3, ASC, and pro-caspase-1.</p> Conclusion <p>DIA exerts a protective effect against CIS-induced testicular toxicity through its antioxidant, anti-inflammatory, and anti-pyroptotic activities, highlighting its potential as a therapeutic candidate targeting the Nrf2/HO-1, NF-κB, and NLRP3/ASC/caspase-1 signaling pathways.</p>