Abstract <p>Two new series of compounds containing azomethine (–CH=N–) and sulfonamide (–SO₂NH–) linkages―(<i>E</i>)-4-[(4-alkoxybenzylidene)amino]-<i>N</i>-(5-methylisoxazol-3-yl)benzenesulfonamides and (<i>E</i>)-4-[(4-alkoxy-3-methoxybenzylidene)amino]-<i>N</i>-(5-methylisoxazol-3-yl)benzenesulfonamides, each of 7 derivatives―were synthesized, and their mesogenic behavior was investigated. Optical polarizing microscopy with a heating stage was used to determine phase transition temperatures, revealing that ten synthesized compounds exhibited nematic mesophases. The transition temperatures decreased with increasing alkyl chain length, while the lateral ortho-methoxyl substitution in the phenyl ring in (<i>E</i>)-4-[(4-alkoxy-3-methoxybenzylidene)amino]-<i>N</i>-(5-methylisoxazol-3-yl)benzenesulfonamides further reduced mesophase stability due to steric hindrance and disrupted molecular packing. The products exhibited enantiotropic nematic mesomorphism, with transition temperatures following an expected trend. Density functional theory calculations provided insights into the molecular geometries, electronic properties, and intermolecular interactions of the synthesized compounds. The HOMO–LUMO energy gaps indicated a higher stability of (<i>E</i>)-4-[(4-alkoxybenzylidene)amino]-<i>N</i>-(5-methylisoxazol-3-yl)benzenesulfonamides compared to (<i>E</i>)-4-[(4-alkoxy-3-methoxybenzylidene)amino]-<i>N</i>-(5-methylisoxazol-3-yl)benzenesulfonamides. Molecular electrostatic potential maps highlighted charge distributions influencing self-assembly and mesophase formation.</p>