Background: SARS-CoV-2 infection has been associated with the increased incidence of acute macular neuroretinopathy (AMN), an infrequent ocular disorder. However, the precise mechanisms underpinning AMN in the context of SARS-CoV-2 infection (AMN-SARS-CoV-2) remain elusive. Methods: In this case-control study 14 patients diagnosed with AMN-SARS-CoV-2 between 2022/12 and 2023/3 were enrolled in this study. 14 SARS-CoV-2-infected individuals without AMN (SARS-CoV-2-no AMN) as control. 14 AMN-SARS-CoV-2 patients were compared with 14 SARS-CoV-2-no AMN. Metabolomic profiling using Ultra-High-Performance Liquid Chromatography-Online Electrospray Mass Spectrometry (UHPLC-OE-MS) revealed significant alterations in serum metabolites in AMN-SARS-CoV-2 patients. Abnormal blood clotting was observed in AMN-SARS-CoV-2 patients, and its relationship with metabolic disorders was studied. Finally, a predictive model for AMN-SARS-CoV-2 was established. Results: 76 upregulated and 42 downregulated metabolites were discovered in AMN-SARS-CoV-2. Notably, arginine metabolism within the urea cycle showed substantial changes, evidenced by variations in ornithine, citrulline, L-proline, and ADAM levels, correlating with abnormal coagulation markers like platelet crit (PCT), fibrinogen degradation products (FDP), and fibrinogen (Fbg). Additionally, increased arginase 1 (AGR1) activity within the urea cycle and reduced nitric oxide synthase (NOS) activity were observed in AMN-SARS-CoV-2. Combining these urea cycle metabolites with coagulation parameters effectively distinguished AMN-SARS-CoV-2 from SARS-CoV-2-no AMN, with an area under the curve (AUC) value of 0.96. Conclusion: The findings of the present study enhance our comprehension of the underlying metabolic mechanisms associated with AMN-SARS-CoV-2 and offer potential diagnostic markers for this uncommon ocular disorder within the context of SARS-CoV-2 infection.