This study successfully employed a commercial package of FLUENT code to solve the three-dimensional flow in a forced-liquid HTLB and an integrated Taguchi OA to optimize the gas hold up for the production of biomass. An L9 orthogonal array was implemented to optimize the factors that affect the flow hydrodynamics in the loop bioreactor, and air inlet velocity, liquid inlet velocity, bubble diameter, and viscosity were chosen as the main parameters. By combining the hydrodynamics and the chemical species transport equation, the biomass production from natural gas was simulated in the HTLB. The results demonstrate the ability of CFD to provide new insights on the biological phenomena that occur in the gas–liquid reactors. The simulation results confirm that a Eulerian formulation is a successful approach to predict the hydrodynamics of the bioreactor because it provides good engineering descriptions and can be used reliably to predict theflowand holdup patterns in such systems. Based on the optimization, the liquid inlet velocity and viscosity were the parameters that had the most significant and insignificant effects on flow behavior in the system, respectively. Under the optimal conditions (Table 8), the simulated and experimental data were in good agreement with the predicted data analyzed by the Taguchi robust design method. Our data indicated that an increase in biomass production occurred under the optimal conditions suggested by the Taguchi design. Thus, the Taguchi optimization technique is a powerful tool to solve indus