A one-pot enantioselective strategy has been developed for the synthesis of chiral 3-alkyl-1,5-functionalized-1,4-diynes. The key step involves an organocatalytic enantioselective conjugate addition of isoxazol-5(4H)-ones to nitroenynes, affording highly enantioenriched intermediates in good yields. Subsequent Zard-type transformation under one-pot conditions enabled the preparation of chiral skipped diynes with good overall yields and excellent enantioselectivities. This study highlights the synthetic versatility of the isoxazol-5(4H)-one scaffold and its value as a platform for accessing structurally diverse and synthetically relevant building blocks.