Reproductive dysfunctions (RDs) characterized by impairment in testicular parameters, and metabolic disorders such as insulin resistance and type 2 diabetes mellitus (T2DM) are on the rise among human immunodeficiency virus (HIV) patients under tenofovir disoproxil fumarate (TDF) and highly active antiretroviral therapy (HAART). These adverse effects require a nanoparticle delivery system to circumvent biological barriers and ensure adequate ARVDs to viral reservoir sites like testis. This study aimed to investigate the effect of TDF-loaded silver nanoparticles (AgNPs), TDF-AgNPs on sperm quality, hormonal profile, insulin-like growth factor 1 (IGF-1), and testicular ultrastructure in diabetic rats, a result of which could cater for the neglected reproductive and metabolic dysfunctions in HIV therapeutic modality. Thirty-six adult Sprague-Dawley rats were assigned to diabetic and non-diabetic (n = 18). T2DM was induced by fructose-streptozotocin (Frt-STZ) rat model. Subsequently, the rats in both groups were subdivided into three groups each (n = 6) and administered distilled water, TDF, and TDF-AgNP. In this study, administration of TDF-AgNP to diabetic rats significantly reduced (p < 0.05) blood glucose level (268.7 ± 10.8 mg/dL) from 429 ± 16.9 mg/dL in diabetic control and prevented a drastic reduction in sperm count and viability. More so, TDF-AgNP significantly increased (p < 0.05) Gonadotropin-Releasing Hormone (1114.3 ± 112.6 µg), Follicle Stimulating Hormone (13.2 ± 1.5 IU/L), Luteinizing Hormone (140.7 ± 15.2 IU/L), testosterone (0.2 ± 0.02 ng/L), and IGF-1 (1564.0 ± 81.6 ng/mL) compared to their respective diabetic controls (383.4 ± 63.3, 6.1 ± 1.2, 76.1 ± 9.1, 0.1 ± 0.01, 769.4 ± 83.7). Also, TDF-AgNP treated diabetic rats presented an improved testicular architecture marked with the thickened basement membrane, degenerated Sertoli cells, spermatogenic cells, and axoneme. This study has demonstrated that administration of TDF-AgNPs restored the function of hypothalamic-pituitary-gonadal axis, normalized the hormonal profile, enhanced testicular function and structure to alleviate reproductive dysfunctions in diabetic rats. This is the first study to conjugate TDF with AgNPs and examined its effects on reproductive indices, local gonadal factor and testicular ultrastructure in male diabetic rats with the potential to cater for neglected reproductive dysfunction in HIV therapeutic modality.