Interleukin-2 (IL-2), is a 15.5-kDa cytokine that is now emerging as a target in drug discovery for novel therapeutic approaches in several autoimmune disorders. In an attempt to identify new inhibitors for the IL-2/IL-2R interaction, virtual screening (VS) was performed. Four different docking programs (GOLD, FlexX, Glide, and LigandFit) in combination with several scoring functions were used to identify novel IL-2/IL-2R interaction inhibitors. VS of a database of 6,000 compounds resulted in the identification of three novel and moderately active hits with IC $$_{50}$$ values ranging from 6.6 to 44.3 $$\upmu $$ M. Furthermore, the effect of these three compounds on the expression of IL-2R $$\alpha $$ was assessed. The three active hits showed dose-dependent inhibitory effects on the expression of IL-2R $$\alpha $$ with an IC $$_{50}$$ range of 5.8 to 140 $$\upmu $$ M. The cytotoxicity of these active hits was assessed using three normal cell-lines: bovine kidney cell-line (MDBK), mouse fibroblast cell-line (3T3), and rat hepatocytes cell-line (CC-1). The compounds were found to have negligible cytotoxicity compared to their IC $$_{50}$$ as IL-2/IL-2R interaction inhibitors. These results demonstrate that our VS protocol can identify novel inhibitors for IL-2/IL-2R interaction that effectively suppress IL-2 production, as well as the expression of IL-2R $$\alpha $$ . Optimization of these molecules could lead to improved and effective anti-inflammatory therapeutics.