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A theoretical study of the mechanism and regioselectivity of 1,3‐dipolar cycloaddition of nitrile oxides to 3‐methylene indolone has been performed by density functional theory at the M06‐2X/6‐311++G(d,p) level of theory. The results indicate that the concerted pathway is more favorable than the stepwise pathway. Investigation of the regioselectivity of this reaction shows that the main product is predicted to be 3,5‐substituted isoxazoline derivatives, which is consistent with experimental observations. The substituent effect of nitrile oxides on the reactivity and regioselectivity were also investigated. The opposite regioselectivity was observed for nitrile oxides with electron‐donating groups (methyl and phenyl) compared with electron‐withdrawing groups (CN and CO2Me). Distortion–interaction energy analysis shows that the reactivity of 1,3‐dipolar cycloaddition of nitrile oxides to 3‐methylene indolone is controlled by both the distortion and interaction energies. Natural population analysis indicates that the carbon atom of the 1,3‐dipole prefers to bond to the terminal carbon atom of the exocyclic double bond of 3‐methylene indolone, forming the 3,5‐substituted isoxazoline product. Frontier molecular orbital analysis shows that the regioselectivity is controlled by the orbital interaction between the lowest unoccupied molecular orbital of the nitrile oxide and the highest occupied molecular orbital of 3‐methylene indolone. [ABSTRACT FROM AUTHOR]