© 2022, The Author(s).The critical function of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis attracted a great interest throughout beyond decades. Inhibitors of human DHODH (hDHODH) have validated efficacy for remedy of many immunological diseases. Brequinar and leflunomide are examples of such compounds. However, most of such immunosuppressive medications suffer from a lot of side effects and accompanied by adverse metabolic disturbances and toxicities. So that, immunomodulation utilizing natural products received the attention of many researchers. In this study, computer-aided molecular docking, molecular dynamic (MD) simulations and biochemical testing were utilized to find new pharmacologically active chemical entities from natural sources to combat immunosuppressive diseases. More specifically, Glide docking was used for a structure-based virtual screening of in-house 3D database of compounds retrieved from some traditionally known immunomodulatory plants surveyed from literature. The top five scored plants were found to be Zingiber officinale, Curcuma longa, Glycyrrhiza glabra, Allium sativum and Olea europaea. In vitro hDHODH inhibitory assays illustrated the ability of Allium sativum and silymarin standard hits; specifically, silibinin, to significantly inhibit the hDHODH enzyme. Molecular docking and MD simulations revealed a strong binding of the discovered hits within the active site. Following that, the most promising hits were tested separately with brequinar in a fixed-ratio combination setting to assess their combined effects on hDHODH catalytic inhibition. The binary combination of silibinin and brequinar revealed that in this combination, brequinar could be utilized at a dose 9.33-fold less when compared to its single-use to produce 99% inhibition for hDHODH enzyme. These findings confirmed that this binary mixture is an excellent combination providing better therapeutic effects and lower side effects.