An eco-efficient and economic method was proposed for the synthesis of different chromenoquinoline-10,12(6H)-dione derivatives via mortar-pestle grinding. This synthetic approach uses a mixture of substituted arylaldehyde, cyclohexane-1,3-dione and 2-amino-4H-chromen-4-one in the presence of environmentally friendly [Et3NH][HSO4]. This approach encompasses a one-pot, three-component synthesis process that employs mortar-pestle grinding. It has several benefits, such as being cost-effective, easy to handle, and short reaction time (30 min). The reaction can be carried out at ambient temperature, and the purification process is short and simple, resulting in excellent yield (70–93%). 1H, 13C NMR, FT-IR, MS analytical data were used for identification of synthesized derivatives. Furthermore, the method is environmentally friendly since it eliminates toxic solvents, column chromatography, and metal catalysts. The constructed 3,5-dichloro and 4-fluoro substituted chromenoquinoline-10,12(6H)-diones showed a good result against the chosen protein. [ABSTRACT FROM AUTHOR]