Lead (Pb) is one of the most common toxic heavy metals. It is a well‐knowntesticular toxicant. Selenium nanoparticles (SeNPs) are a more effective formof elemental selenium that reduces drug‐induced toxicities. This study aimedto study the possible ameliorating effect of SeNPs on the toxicological andmorphological changes in testes of lead acetate intoxicated rats. The study wasconducted on 40 adult male albino rats divided into four groups; control,SeNPs‐treated, lead acetate‐treated, lead acetate and SeNPS treated groups.The concurrent treatment of lead acetate‐exposed rats with SeNPs (0.1 mg/kg/day) for 12 weeks significantly lowered the blood and testicular lead levels, in-creased serum testosterone, and decreased luteinizing hormone and follicle‐stimulating hormone to approach control values. In addition, it improvedthe histopathological, and ultrastructural alterations of the testes and improvedthe immunohistochemical expression of the c‐kit. This was accompanied bymaintenance of the testicular oxidant/antioxidant balance and reversing thelead‐induced disrupted calmodulin‐related genes expression in testicular tissuein the form of downregulation of CAMMK2 and MAP2K6 and upregulationof CXCR4 genes. There was a strong positive correlation between testicularmalondialdehyde and MAP2K6 expression level as well as a strong positivecorrelation between CXCR4 gene expression and the C‐kit area %. In conclu-sion, SeNPs can be considered as a potential therapy for a lead‐inducedtesticular injury.