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Abstract Introduction We studied the correlation of central macular fluid volume (CMFV) and central subfield thickness (CST) with best-corrected visual acuity (BCVA) in treatment-naïve eyes with diabetic macular edema (DME) 1 month after anti-vascular endothelial growth factor (VEGF) therapy. Methods This retrospective cohort study investigated eyes that received anti-VEGF therapy. All participants underwent comprehensive examinations and optical coherence tomography (OCT) volume scans at baseline (M0) and 1 month after the first treatment (M1). Two deep learning models were separately developed to automatically measure the CMFV and the CST. Correlations were analyzed between the CMFV and the logMAR BCVA at M0 and logMAR BCVA at M1. The area under the receiver operating characteristic curve (AUROC) of CMFV and CST for predicting eyes with BCVA $$\ge$$ ≥ 20/40 at M1 was analyzed. Results This study included 156 DME eyes from 89 patients. The median CMFV decreased from 0.272 (0.061–0.568) at M0 to 0.096 (0.018–0.307) mm3 at M1. The CST decreased from 414 (293–575) to 322 (252–430) μm. The logMAR BCVA decreased from 0.523 (0.301–0.817) to 0.398 (0.222–0.699). Multivariate analysis demonstrated that the CMFV was the only significant factor for logMAR BCVA at both M0 (β = 0.199, p = 0.047) and M1 (β = 0.279, p = 0.004). The AUROC of CMFV for predicting eyes with BCVA $$\ge$$ ≥ 20/40 at M1 was 0.72, and the AUROC of CST was 0.69. Conclusions Anti-VEGF therapy is an effective treatment for DME. Automated measured CMFV is a more accurate prognostic factor than CST for the initial anti-VEGF treatment outcome of DME.