Calcined clays and calcium carbonates can be used to reduce clinker factor in blended cements, offering significant economic and environmental benefits. Limestone calcined clay cements (LC3) combine them as supplementary cementitious materials (SCMs) for delivering a sustainable alternative to conventional Ordinary Portland Cement products, with envisioned applications in construction and rehabilitation of historical buildings.This study reports a chemometric approach to the development of LC3 mortars, targeting to minimize clinker content while maintaining or improving the technical characteristics. To evaluate their performance, apparent density, modulus of elasticity, open porosity, water absorption, flexural and compressive strength have been considered as responses. Multiple Linear Regression (MLR) and Principal Component Analysis (PCA) were employed in a three-step mixture-process design allowing to obtain LC3 mixtures with a 21 wt.% reduction in clinker while achieving notable enhancements in the physical properties (open porosity -9% and water absorption -10%), along with commendable increases in compressive strength (+17%) when compared to benchmark mortars produced without SCMs. The successful integration of multivariate techniques in designing sustainable building materials is showcased, highlighting the potential of chemometric methodologies to reduce the environmental impact as well as to increase the performance of building materials.