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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 <i>B. tequilensis</i> enzymes. The experiments were guided by two optimization methods, namely, 2^k factorial and response surface methodology (RSM). The 2^k 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), <i>B. tequilensis</i> 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 <i>B. tequilensis</i> 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 <i>B. tequilensis</i> surface reactions of carbonic anhydrase (CA) and urease enzyme with calcium in cement and sequestered CO₂ during the curing time.