Protein kinase C theta (PKCθ) is a unique PKC isoform distinguished by its specific cellular localization in T cells. It plays a critical non-redundant role in regulating T cell activation and is implicated in various autoimmune and inflammatory disorders. Notably, PKCθ is selectively required for detrimental immune responses while being dispensable for beneficial ones; thus, inhibiting PKCθ could specifically reduce detrimental immunity. Moreover, PKCθ has been linked to tumour progression, making it a promising target for cancer therapy. Herein we report the discovery of three new natural compounds as potent PKCθ inhibitors. A comprehensive multistep virtual screening protocol was employed to screen the InterBioScreen database (67,749 compounds) against PKCθ. Molecular docking yielded 40 hits that were subjected to molecular dynamics simulations to assess their stability of binding. In addition to monitoring persistent ligand-protein interactions, binding free energies for the complexes were calculated. Five top compounds that formed stable complexes with PKCθ in silico were then purchased to test their inhibitory activity in vitro. Three of the compounds demonstrated potent, low submicromolar activity against PKCθ, namely STOCK1N-80,922 and STOCK1N-97,911 (IC₅₀ around 0.10 µM) and STOCK1N-93,016 (IC₅₀ around 0.3 µM). The binding free energy decomposition suggests that strong van der Waals/lipophilic binding interactions contribute to the potency of the three compounds. Moreover, these three compounds are predicted to be drug-like and orally bioavailable and, thus, represent promising candidates for further investigation as PKCθ inhibitors. The overall results give insights that may be valuable for the development of PKCθ inhibitors as potential therapeutics.