Medicinal plants are currently receiving a lot of emphasis in the fish diet due to their high nutritional and economic worth. The current study is a pioneer attempt to evaluate the effect of Hyphaene thebaica (HT) powder, namely doum palm fruit powder, as a dietary supplement on the reproductive performance, biochemical, and growth parameters, besides histological features of gonads of African catfish (Clarias gariepinus L.). Moreover, its antifungal potential against Candida albicans was also assessed in vivo and in vitro. Fish (n = 90; body weight: 181.49 ± 0.38 g for male and 181.93 ± 0.40 g for female) were randomly distributed into three groups [30 fish/group (15 males: 15 females), 10 fish/replicate]. For 70 days, the fish were fed diets supplemented with three levels of HT 0, 1, and 1.5% (HT0, HT1, and HT1.5), respectively, where the HT0 group served as a control. The results revealed that the growth variables (final body weight and body weight gain) and serum growth hormone level were significantly elevated (P < 0.05) in females of HT-fed groups in a dose-dependent manner more than the males. The gonadosomatic index values showed marked enhancement (P < 0.05) in both males and females of the HT1.5 group compared to other groups. Females had a higher serum level of calcium and potassium than males (P < 0.01). Males fed on a diet supplemented with HT1.5 showed an increase in the serum level of calcium. Dietary HT (HT1.5 diet followed by HT1 diet) showed a notable enhancement in the concentrations of testosterone and 17β estradiol for males (P < 0.05). Histologically, an improvement in the tissue architecture of gonads was observed in HTfed groups for both males and females. The lowest cumulative mortality after the C. albicans challenge was observed in males and females of the HT1.5 group (13.33 and 20%), followed by the HT1 group (26.67 and 33.33%), respectively. Moreover, HT showed an in vitro antifungal capability with an inhibitory zone of 14.33 and 18.66 mm for HT (1 and 1.5 mg/mL), respectively. The outcomes showed that HT might be a feed supplement for the sustainable aquaculture sector to boost growth and reproductive performance and protect C. gariepinus against C. albicans infection.