Tick‐borne encephalitis virus (TBEV), a member of the genus Flavivirus, is the leading cause of arboviral neuroinfections in Europe. Only a few classes of the nucleoside and non‐nucleoside inhibitors were investigated against TBEV reproduction. Paving the way to previously unexplored areas of anti‐TBEV chemical space, we assessed the inhibition of TBEV reproduction in the plaque reduction assay by various compounds derived from cyanothioacetamide and cyanoselenoacetamide. Compounds from seven classes, including 4‐(alkylthio)‐2‐aryl‐3‐azaspiro[5.5]undec‐4‐ene‐1,1,5‐tricarbonitriles, 3‐arylamino‐2‐(selenazol‐2‐yl)acrylonitriles, ethyl 6‐(alkylseleno)‐5‐cyano‐2‐oxo‐1,2‐dihydropyridine‐3‐carboxylates, 6‐(alkylseleno)‐2‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carbonitriles, 2‐(alkylseleno)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carbonitriles, 8‐selenoxo‐3,5,7,11‐tetraazatricyclo[7.3.1.0^2,7]tridec‐2‐ene‐1,9‐dicarbonitriles, and selenolo[2,3‐b]quinolines, inhibited TBEV reproduction with EC₅₀ values in the micromolar range while showing moderate cytotoxicity and no inhibition of enterovirus reproduction. Thus, new scaffolds with promising anti‐TBEV activity were found.