The present study aimed to optimize the phenolic and antioxidant-rich extract from the nutmeg (Myristica fragrans Houtt) by using a two-factor 26-run central composite design-based response surface methodology tool. The selected parameters were extraction period (2 to 5 days), solvent-to-water ratio (v/v) (50–100%), and type of solvent (acetone or ethanol). The optimized extract at conditions of 3.14 days incubation and 68% (v/v) acetone showed total phenolic content (TPC), total flavonoid content (TFC), and DPPH antioxidant assay as 376.38 mg GAE/g DW, 34.40 mg QUE/g DW and 842.46 mg AAE/g DW, respectively. Among the nineteen (19) compounds identified by the LC–MS, myristicin (37.74%) was found to be the highest. Nine (9) alkane-fatty acyl compounds were determined by the GC–MS analysis, as well. Additionally, SEM and XRD revealed sheet-like anatomy with the presence of Carbon (C), Oxygen (O) and Potassium (K). The study presented a unique approach to optimizing phenolic-rich antioxidant extracts from nutmeg using response surface methodology, offering valuable insights for more efficient extraction of bioactive compounds with minimal resource waste and potentially enhancing the utilization of nutmeg's nutraceutical properties.