Lagenaria siceraria (bottle gourd) fruit is highly celebrated for its nutritional as well as therapeutic properties. The present study was undertaken with the aim of exploring an efficient green solvent-free microwave-assisted extraction method for bioactives from this fruit. Optimization was done according to response surface methodology (RSM), where microwave power (W) and time (s) were independent factors, and percent extraction yield, total phenolic content (TPC), total flavonoid content (TFC), 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant potential (FRAP) and iron chelating activity (ICA) were the responses. TPC, TFC, DPPH radical scavenging activity, FRAP and ICA were highest at 480 W and 60 s. The TPC was 288.9 mg GAE · g−1 DW (milligram gallic acid equivalent per gram dry weight), TFC was 214.1 mg RE · g−1 (rutin equivalent per gram DW), anti-radical activity was 32.96%, FRAP was 289.7 mg AAE · g−1 (mg ascorbic acid equivalents per gram) and ICA was 19.52%. The results of the study thus demonstrate that the solvent-free microwave-assisted extraction method, which utilised an optimum power of 480 W and a time of 60 s, is an effective and green method for extraction of antioxidant compounds from bottle gourd fruit.