Objective Ipomoea genus is an excellent source of lysergol which is used as a hypotensive and psychrotopic analgesic. Microwave-assisted extraction (MAE) was employed to extract lysergol from Ipomoea seeds, and response surface methodology (RSM) was applied to predict optimum conditions for extraction. Methodology Box-Behnken statistical design was used to monitor the effect of independent variables like temperature (A-50°C, 60°C, and 70°C), power (B-240, 350, and 700 W), and time (C-10, 20, and 30 min) on a dependent variable/percent yield of lysergol when microwaves were applied. Correlation analysis of the mathematical regression model indicated that a quadratic polynomial model could be employed to optimize the process. Results The optimum extraction conditions in order to obtain the highest lysergol yield were temperature (60°C), power (350 W), and time (20 min). The average actual yield of lysergol under the optimum conditions was found to be 78.0%, whereas the predicted yield under similar conditions was 85.374%. Conclusions The results verified our experiments and successful application of RSM to MAE of lysergol from Ipomoea seeds. The percentage purity of the extracted lysergol was found to be 90% with reference to standard lysergol (97%) with the help of RP HPLC-UV.