Determination of physiological loads in human lumbar spine is critical for understanding the mechanisms of lumbar diseases and for designing surgical treatments. Computational models have been used widely to estimate the physiological loads of the spine during simulated functional activities. However, various assumptions on physiological factors such as the intra-abdominal pressure (IAP), centers of mass (COMs) of the upper body and lumbar segments, and vertebral centers of rotation (CORs) have been made in modeling techniques. Systematic knowledge of how these assumptions will affect the predicted spinal biomechanics is important for improving the simulation accuracy. In this paper, we developed a 3D subject-specific numerical model of the lumbosacral spine including T12 and 90 muscles. The effects of the IAP magnitude and COMs locations on the COR of each motion segment and on the joint/muscle forces were investigated using a global convergence optimization procedure when the subject was in a weight bearing standing position. The data indicated that the line connecting the CORs showed a smaller curvature than the lordosis of the lumbar spine in standing posture when the IAP was 0 kPa and the COMs were 10 mm anterior to the geometric center of the T12 vertebra. Increasing the IAP from 0 kPa to 10 kPa shifted the location of CORs toward the posterior direction (from 1.4 ± 8.9 mm anterior to intervertebral disc (IVD) centers to 40.5 ± 3.1 mm posterior to the IVD centers) and reduced the average joint force (from 0.78 ± 0.11 Body weight (BW) to 0.31 ± 0.07 BW) and overall muscle force (from 349.3 ± 57.7 N to 221.5 ± 84.2 N). Anterior movement of the COMs from −30 mm to 70 mm relative to the geometric center of T12 vertebra caused an anterior shift of the CORs (from 25.1 ± 8.3 mm posterior to IVD centers to 7.8 ± 6.2 mm anterior to IVD centers) and increases of average joint forces (from 0.78 ± 0.1 BW to 0.93 ± 0.1 BW) and muscle force (from 348.9 ± 47.7 N to 452.9 ± 58.6 N). Therefore, it is important to consider the IAP and correct COMs in order to accurately simulate human spine biomechanics. The method and results of this study could be useful for designing prevention strategies of spinal injuries and recurrences, and for enhancing rehabilitation efficiency.