Nowadays, with increased demand for aggregates for concrete and an awareness of the need of protecting natural resources, experts are becoming increasingly interested in waste material as a building material substitute. However, the compressive strength is influenced by the composition of concrete. In this study, the compressive strength of concrete under substitution using waste from cockle shells and glass was investigated using Response Surface Methodology (RSM). Central Composite Design (CCD) based on RSM was used to assess the influence of epoxy resin, cockle shells powder, and glass powder on compressive strength responses. RSM developed first-order and second-order mathematical models with findings from experimental design. Analysis of variance was used to determine the correctness of CCD's mathematical models. Desirability analysis was then employed to optimize epoxy resin, cockle shells powder, and glass powder yielding maximum compressive strength. The RSM analysis revealed that the empirical results fit well into linear and quadratic models of concrete compressive strength. The mixing components will produce cement with compressive strength in each formulation of 54.71 MPa (4.88% epoxy resin and 4.0% cockle shells powder), 47.82 MPa (6.85% epoxy resin and 8.0% glass powder), 147.0 MPa, (4% cockle shells powder and 8% glass powder), and 56.08 MPa (4.4% epoxy resin, 4.0% cockle shells powder, and 8.0% glass powder). The results confirmed that a reasonable compressive strength of concrete could be achieved using epoxy resin, cockle shells powder, and glass powder.