This study presents modeling and optimization of ultrasound-assisted extraction (UAE) of Melastoma malabathricum with the objective of evaluating its phytochemical properties. This one-factor-at-a-time (OFAT) procedure was conducted to screen for optimization variables whose domains included extraction temperature (X_ET), ultrasonic time (X_UT), solvent concentration (X_SC), and sample-to-liquid ratio (X_SLR). Response surface methodology (RSM) coupled with Box–Behnken design (BBD) was applied to establish optimum conditions for maximum antioxidant extraction. Modeling and optimization conditions of UAE at 37 kHz, X_ET 32 °C for X_UT 16 min and dissolved in an X_SC 70% ethanol concentration at a X_SLR 1:10 ratio yielded scavenging effects on 2,2-diphenyl-1-picryl-hydrazyl (DPPH) at 96% ± 1.48 and recorded values of total phenolic content (TPC) and total flavonoid content (TFC) at 803.456 ± 32.48 mg GAE (gallic acid equivalents)/g, and 102.972 ± 2.51 mg QE (quercetin equivalents)/g, respectively. The presence of high flavonoid compounds was verified using TWIMS-QTOFMS. Chromatic evaluation of phytochemicals using gas chromatography–mass spectrometry (GC–MS) revealed the presence of 14 phytocompounds widely documented to play significant roles in human health. This study provides a comparative evaluation with other studies and may be used for validation of the species’ potential for its much-acclaimed medicinal and cosmeceutical uses.