Developing polyols from abundant and renewable biomass resources is an important topic for polymer synthesis. In this work, the Response Surface Methodology (RSM) was applied to a novel oxypropylation case study, almond shell (AS), an agroindustry lignocellulosic by-product. Mathematical models were developed to determine responses maximizing the reaction efficiency to yield polyols with specific technical requirements (polyols suitable for rigid polyurethane foams; hydroxyl index between 300 and 800 mgKOH/g, and viscosity below 300 Pa*s). In a general way, the properties of the obtained polyols were within the range of the ones currently used commercially, reinforcing the interest to exploit lignocellulosic bio-residues for polyol synthesis. For simultaneous minimization of homopolymer content and unreacted biomass, values of 14.0% and 14.1% were achieved, respectively. This was attained using a formulation with an AS/PO ratio of 20.1/79.9 g/ml and a catalyst content of 3.14%, giving rise to a polyol with an hydroxyl index of 392.1 KOH/g and a viscosity of 107.4 Pa*s. Overall, the advantages of using RSM to better understand complex reactive systems and the interest to use these statistical approaches as decision-making tools was demonstrated.