This paper aims to fabricate and optimize eco-sustainable cement brick using different sizes of clay brick waste (CBW). The prime input factors of mixtures were clay brick powder (CBP) as a binder, fine-clay brick (FCB) as a fine aggregate, and coarse-clay brick (CCB) as a coarse aggregate, whereas the compressive strength was the main response of the generated eco-sustainable bricks. This was accomplished by utilizing the central composite design (CCD) and Response Surface Methodology (RSM) with Minitab-19. Twenty mixtures with CBW were generated and experimentally evaluated utilizing CCD concept in RSM. A multi-objective optimization approach was applied to obtain the optimum results for the input parameters. Based on an experimental program, the optimum mixtures were selected to investigate the physical and durability properties of the produced brick. The SEM test was also performed to determine the effect of the CBW particles on the microstructure of the brick. The life cycle assessment of mixtures is also performed in terms of global warming potential. The optimization showed that the input components CBP, FCB, and CCB had average optimum values of 21%, 0%, and 9.09%, respectively. The experimental results showed that employing CBW yields a durable and high freeze-thaw resistance of the eco-sustainable brick despite its high porosity and absorption. Furthermore, using cement brick with CBW particles is acknowledged as a more environmentally beneficial combination. The proposed models can speed up the process of mix design by using different sizes of brick waste to get the optimum eco-friendly cement brick properties.