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Objective: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans‐synaptic degeneration, and determine its clinical relevance. Methods: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed‐effects linear regression models were used. Results: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non‐AON cohort (−0.76% vs −0.22% per year [p = 0.01] for occipital GM, −1.83% vs −0.32% per year [p = 0.008] for calcarine GM, −1.17% vs −0.67% per year [p = 0.02] for thalamus), whereas rates of whole‐brain, cortical GM, non‐occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON‐induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole‐brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. Interpretation: These results provide in‐vivo evidence for anterograde trans‐synaptic degeneration following AON in PwMS, and suggest that trans‐synaptic degeneration may be related to clinically‐relevant visual outcomes. ANN NEUROL 2023;93:76–87 [ABSTRACT FROM AUTHOR]