This research aimed to optimize the compressive strength of bio-foamed concrete brick (B-FCB) via a combination of the natural sequestration of CO2 and the bio-reaction of B. tequilensis enzymes. The experiments were guided by two optimization methods, namely, 2k factorial and response surface methodology (RSM). The 2k factorial analysis was carried out to screen the important factors; then, RSM analysis was performed to optimize the compressive strength of B-FCB. Four factors, namely, density (D), B. tequilensis concentration (B), temperature (T), and CO2 concentration, were selectively varied during the study. The optimum compressive strength of B-FCB was 8.22 MPa, as deduced from the following conditions: 10% CO2, 3 × 107 cell/mL of B, 27 °C of T and 1800 kg/m3 of D after 28 days. The use of B. tequilensis in B-FCB improved the compressive strength by 35.5% compared to the foamed concrete brick (FCB) after 28 days. A microstructure analysis by scanning electronic microscopy (SEM), energy dispersive X-ray (EDX) and X-ray diffraction analysis (XRD) reflected the changes in chemical element levels and calcium carbonate (CaCO3) precipitation in the B-FCB pores. This was due to the B. tequilensis surface reactions of carbonic anhydrase (CA) and urease enzyme with calcium in cement and sequestered CO2 during the curing time.