The main focus of present study is to optimize the extraction parameters for maximum yield of biomass, β-carotene and chlorophyll content and their antioxidants from Kappaphycus alvarezii by response surface methodology (RSM) along with adaptive neuro-fuzzy inference system (ANFIS). Central composite rotatable design of RSM was applied to optimize the effect of microwave-assisted extraction (MAE) parameters. In this way, four parameters, such as methanol concentration (X1: 65–80%), microwave power (X2: 15–20%), radiation induced temperature (X3: 45–60 °C) and radiation exposure time (X4: 7.5–15 min) at five levels were selected. Optimal conditions were found as X1 = 80%, X2 = 20%, X3 = 45 °C and X4 = 12.5–14.5 min, under this condition, % yield of biomass (y1) = 86.231–87.212%, β-carotene and chlorophyll content (y2) = 77.348–82.841 mg/gm, %DPPHsc (y3) = 69.362–72.768%, %ABTSsc (y4) = 66.282–70.621%, FRAP (y5) = 62.654–64.381 μg mol (Fe(II))/g has been obtained. Also, optimized values of MAE parameters were compared and verified with ANFIS. Further, the major bioactive compounds present in the optimally obtained extract of K. alvarezii was identified through FTIR, gas chromatography-mass spectrum and HPLC. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.