BackgroundErectile dysfunction (ERDF) has been implicated as an adverse effect of Paroxetine. Sildenafil (Viagra) is a conventional currently used in the management of this ailment but with side effects. Carpolobia lutea (CL) is a medicinal plant, traditionally explored and established for its aphrodisiac potential. Aim of the StudyThe study aims to investigate the effect of Carpolobia lutea Extract (CLE) on ERDF rats induced by paroxetine at the molecular level and its phytocompounds’ interaction with proteins linked to the erection pathway. MethodsForty-eight adult male Wistar rats were randomly grouped into six experimental groups: normal control, (20 mg/kg PI- ERDF + 1 ml distilled water) and treated groups (10 mg/kg Sildenafil, 50 mg/kg of CLE, 100 mg/kg of CLE and 200 mg/kg of CLE. Rats were administered paroxetine for five days before their sexual behaviour was examined through mounting frequency and latency when introduced to female rats. Antioxidant assays (DPPH, FRAB and TBARS) were performed over the 21-day experiment, and molecular investigations (in vivo and in silico) on ERDF-linked genes were conducted. ResultsCLE has good in vitro antioxidant content. Paroxetine upregulated the expressions of phosphodiesterase-5, arginase, acetylcholinesterase, AMP deaminase and interleukin-6 relative to control. However, CLE downregulated these proteins and upregulated Nrf2, Androgen receptor, and Luteinizing hormone compared to PI- ERDF. CLE-phytocompounds like quercetin favourably interacted with phosphodiesterase-5 and nitric oxide synthase. ConclusionThe findings suggest that Carpolobia lutea leaf's phytocompounds show potential as a therapeutic agent in ERDF management.