The main objective of this study was to optimize process factors viz. microwave power, irradiation time, and liquid-to-solid ratio for the microwave-assisted hydrothermal treatment of coffee husk biomass. The effect of factors on lignin removal, and cellulose recovery was examined using response surface methodology (RSM) of central composite design (CCD); the optimal pretreatment conditions were selected at a microwave power (800 W), irradiation time (10 min), and liquid-to-solid ratio (10.94 ml/g). The chemical composition of treated coffee husk was found to be 2.23 ± 0.29, 8.53 ± 0.63, 28.08 ± 0.46, 46.07 ± 1.02, and 15.09 ± 0.42 wt% for ash, extractives, lignin, hemicellulose, and cellulose, respectively. The experimental results were validated by comparing the actual value with the predicted value at the confirmation node and verified within the 95% prediction interval (PI) for the fitness of the optimal results. The model was verified as the best for improving delignification and cellulose yield. The coefficient of determination (R2), analysis of variance (ANOVA), response plots, and optimization nodes were used to examine the model’s statistical performance and experimental results. The efficacy of pretreatment for delignification (5.9%) and cellulose recovery (59.85%) was achieved at optimal conditions. The microwave-assisted hydrothermal pretreatment method is able to produce cellulose-rich coffee husk residues. The method is simple, cheap, operated at mild conditions, and eco-friendly green route for producing high-added-value cellulose from wasted coffee husk.