This study systematically investigated the effect of meso-substituents on the antiaromaticity of S2O2Iphs. Through a comprehensive analysis integrating experimental 1 H NMR data and multiple computational approaches (NICS, GIMIC, HOMA/HOMAc, and AV1245/AVmin), we demonstrated that the steric demands of meso-substituents critically influence antiaromaticity through their effect on the tilt angle between the substituents and the isophlorin macrocycle.