The present study was conducted to assess the efficacy of a novel curcumin derivative (NCD) versus Tadalafile in erectile signaling. The study was conducted on 15 control male rats and 75 diabetic male rats divided into the following groups:, diabetic, curcumin, NCD, Tadalafile and NCD combined with Tadalafile . Cavernous tissue gene expression levels of heme oxygenase-1 (HO-1), Nrf2, NFК-β, and p38, enzyme activities of heme oxygenase (HO) and nitric oxide synthase (NOS), cGMP and intracavernosal pressure (ICP) were assessed. Results showed that 12 weeks after induction of diabetes, erectile dysfunction (ED) was confirmed by the significant decrease in ICP, a significant decrease in cGMP, NOS, HO enzyme activities, a significant decrease in HO-1 gene and a significant elevation of NFК-β, p38 genes. Administration of all therapeutic interventions led to a significant elevation in ICP, cGMP levels, a significant increase in HO-1 and NOS enzymes, a significant increase in HO-1, and Nrf2 gene expression, and a significant decrease in NFК-β, p38 gene expression. NCD or its combination with Tadalafile showed significant superiority and more prolonged duration of action. In conclusion, NCD could enhance erectile function with more efficacy and more prolonged duration of action.