Background: paclitaxel (PAC) is a powerful chemotherapy; however, it lacks a focused action resulting in serious side effects. Melatonin (MLT) has potent antioxidant and cell-modulating abilities. Pinostrobin (PN) is an essential dietary flavonoid with numerous pharmacological potentials. This research aimed to assess the ameliorative role of MLT and PN on the testicular damage caused by paclitaxel in rats. Subjects and Methods: Fifty-four adult male albino rats were randomly separated into six equal groups; Control group, PN group, MLT group, PAC group, PAC+PN group, and PAC+ MLT group. After 30 days of treatment blood samples were collected for laboratory analysis and the testes were subjected to biochemical, immunohistochemical, and histological study. Results: Paclitaxel significantly decreased the serum testosterone level and lowered catalase (CAT) and superoxide dismutase (SOD) activities in the testicular tissues while increasing the level of malondialdehyde (MDA) in comparison to rats used as controls. On the other hand, blood testosterone and antioxidant enzyme levels were markedly increased in rats when MLT or PN was co-administered with PAC. Seminiferous tubule disarray and spermatogenic cell degradation were visible in the H&E-stained sections from the PAC group. Broad interstitial areas were also noted with few pyknotic Leydig cells. However, the groups receiving MLT or PN in line with PAC displayed restoration of the normal histological structure of the testicular tissue. The immunohistochemical results showed negative Bcl-2 immunoreaction and noticeable positive TNF-α expression in PAC-exposed rats. PAC+PN group presented moderate positive Bcl-2 immune reactivity and moderate reduction in TNF-α expression whereas, PAC+MLT group presented intense positive Bcl-2 and minimal TNF-α immuno-reactivity. Conclusion: Administration of MLT or PN to PAC exposed rats can protect the testicular tissues from the injurious effects of PAC by means of the anti-apoptotic and antioxidant qualities. However, administration of MLT was more efficient