The synthesis of novel isoxazolo [5,4-b]pyrano[2,3-f]quinoline hybrids has been achieved through a one-pot three-component reaction of 3-methyl-7,8-dihydroisoxazolo [5,4-b]quinolin-5(6H)-one, isatins or aromatic aldehydes and malononitrile in the presence of a base at ambient temperature. The reaction occurred through a domino Knoevenagel-Michael type addi-tion-O-cyclization sequence in a single transformation to afford the products in excellent yields. One of the isoxazolo [5,4b]pyrano [2,3-f]quinoline was found to be highly sensitive towards picric acid with a lower limit of detection of 1.2 μM and quenching constant of 2.