AbstractThe present study aimed to identify the possible protective effect of diacerein (DIA) on gentamicin (GNT)‐induced parotid toxicity in rats. DIA was administered in the presence and absence of GNT. Thirty‐two Wistar adult male rats were randomly arranged into four groups: control, DIA (50 mg/kg/day), GNT (100 mg/kg) and GNT+DIA groups for 8 days. Parotid oxidative stress parameters, besides inflammatory and apoptotic biomarkers, were evaluated. Salivary flow rate, transient receptor potential canonical 1 (TRCP1), and C/EBP homologous protein (CHOP) in parotid tissue were measured. A parotid histopathological examination and an interleukin‐1 beta (IL‐1β) immunohistochemical study were also performed. GNT significantly increased parotid oxidative stress, inflammatory, apoptotic and CHOP biomarkers with decreased salivary flow rate and TRCP1 level. A histopathological picture of parotid damage and high IL‐1β immunoexpression were detected. DIA significantly normalized the distributed oxidative, inflammatory and apoptotic indicators, CHOP and TRCP1, with a prompt improvement in the histopathological picture and a decrease in IL‐1β immunoexpression. These results reported that DIA protects against GNT‐induced parotid toxicity via modulation of TLR4/NF‐κB/IL‐1β and TRPC1/CHOP signalling pathways.