Phosphodiesterase type 5 (PDE5) is a cyclic nucleotide-hydrolyzing enzyme that plays essential roles in the regulation of second messenger cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) produced in response to various stimuli. Pharmacological inhibition of PDE5 has been shown to have several therapeutic uses, including treating cardiovascular diseases and erectile dysfunction. In search of PDE5A inhibitors with safer pharmacokinetic properties, computational analyses of the binding propensity of fifty natural compounds comprising flavonoids, polyphenols, and glycosides were conducted. Molecular dynamics simulation coupled with Molecular mechanics with generalized Born and surface area solvation (MM/GBSA) showed that verbascoside may inhibit the activity of PDE5 with a comparative binding energy (ΔG) of −87.8 ± 9.2 kcal/mol to that of the cocrystal ligand (PDB ID: 3BJC), having ΔG = −77.7±4.5 kcal/mol. However, the other top compounds studied were found to have lower binding propensities than the cocrystal ligand WAN: hesperidin (ΔG = −33.8 ± 3.4 kcal/mol), rutin (ΔG = −23.6 ± 26.3 kcal/mol), caftaric acid (ΔG = −21.2 ±3.6 kcal/mol), and chlorogenic acid (ΔG = 6.0 ± 16.5 kcal/mol). Therefore, verbascoside may serve as a potential PDE5A inhibitor while hesperidin, rutin, and caftaric acid may provide templates for further structural optimization for the designs of safer PDE5 inhibitors.