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Phosphodiesterase 4B is an important enzyme belonging to the phosphodiesterase family, playing a role in regulating the levels of cyclic AMP in cells. Phosphodiesterase 4B degrades cyclic AMP, a crucial signaling molecule involved in numerous biological processes, including inflammation regulation. Recently, the search for potential inhibitors with fewer side effects and high biological activity in valuable medicinal plants has drawn the attention of current scientists. Various in silico methods have been applied to reduce costs and time for experimental studies. In this study, an in silico screening involving a set of 131 natural compounds sourced from Prinsepia utilis species was conducted. These compounds were docked into the active site of the phosphodiesterase 4B protein. As a result, 10 compounds exhibited the most potential inhibitory activity against phosphodiesterase 4B, including 2α-O-trans-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid, 2α-O-cis-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid, cyanidin-3-O-rutinoside, delphinidin-3-O-rutinoside, peonidin-3-O-rutinoside, rutin, isorhamnetin-3-O-rutinoside, kaempferol 3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside-7-O-β-D-glucopyranoside, kaempferol 3-O-α-L-rhamnopyranosyl-(1→6) [α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside, quercetin 3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside were identified through molecular docking simulations. Subsequently, molecular dynamics simulations were performed on these complexes, revealing significant findings regarding their stability. Furthermore, MM–GBSA calculations indicated that the potential compounds had stronger binding free energies than the reference inhibitor. Finally, the selected compounds were subjected to toxicity prediction, showing noteworthy results with large LD50 values and safe toxicity levels. Therefore, these compounds could be potential candidates for further experimental studies as phosphodiesterase 4B inhibitors.