Purpose The ocular choroid is a sensitive biomarker of vascular perfusion in optic neuritis (ON) patients due to its vascular structures. The purpose of this study was to evaluate alterations in sub-macular choroidal thicknesses (sub-MCT) in aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) sero-positive neuromyelitis optica spectrum disease (AQP4-IgG+/NMOSD) and isolated ON (ION) patients using optical coherence tomography (OCT). Methods A total of 208 ON patients (275 eyes) and healthy controls (HCs) who underwent sub-MCT and retinal microstructure detection with OCT were enrolled in this study. Results Among all the ON patients, 102 (49.0%) cases were identified as serum AQP4-IgG-positive, with 106 (51.0%) cases being negative, excluding multiple sclerosis as the ION cohort. The sub-MCT in the AQP4-IgG+/NMOSD patients decreased in 0-6 months after ON attacks. However, for the ION cohort, the sub-MCT decreased in 0-2 months and then stayed normal or slightly increased in 2-4 months after the first ON attack, finally sharply decreasing after 6 months. For unilateral AQP4-IgG+/NMOSD patients, eyes without ON also presented retinal layer thinning and sub-MCT slight reduction independent of ON attacks. Conclusions The sub-MCT in AQP4-IgG+/NMOSD patients were reduced at all stages of ON, which distinguished the ION patients as decreasing only at chronic stage of ON. It implied that ocular vascular hypoperfusion plays a potential role in ON pathogenesis and the different patterns could be caused by the distinct pathogenesis of AQP4-IgG+/NMOSD and ION.