PURPOSE: To investigate the clinical characteristics of early-onset optic neuritis (ON) following the corona virus disease 2019 (COVID-19) Omicron variant and explore the possible pathophysiological mechanisms. METHODS: This was a retrospective, observational study. All enrolled patients with ON following the COVID-19 Omicron variant were followed for at least 6 weeks to observe their clinical characteristics and prognostic factors and to analyze the factors influencing earlier or later occurrence of ON following the COVID-19 Omicron variant. RESULTS: A total of 47 eyes from 47 patients (22 males [46.8%] and 25 females [53.2%]) were enrolled in this study and divided into late- and early-onset groups. Compared to the late-onset group, the early-onset group had a higher dual-seronegative antibody status (21.43% vs. 63.16%, P = 0.004) and a higher CD8 + /lymphocyte percentage (23.3% [20.1%, 28.3%] vs. 31.0% [29.8%, 34.2%], P = 0.008). Furthermore, Pearson's partial correlation analysis showed that dual-seronegative antibody status (adjusted r = 0.800, adjusted P = 0.001) and CD8 + /lymphocyte percentage (adjusted r = 0.747, adjusted P = 0.002) were independently associated with early-onset ON following the COVID-19 Omicron variant. Further partial correlation analysis also showed that a swollen optic disc (r = -0.347, P = 0.035) was the only factor independently associated with final best-corrected visual acuity (BCVA). CONCLUSIONS: Earlier onset of ON following COVID-19 Omicron variant indicated a higher CD8 + /lymphocyte percentage in the serum and a greater possibility of dual-seronegative antibody status. Whether ON following the COVID-19 Omicron variant occurred earlier or later did not independently affect final BCVA, and the only independent factor predicting better final BCVA was a swollen optic disc.