Adjacent segment disorders are prevalent in patients following a spinal fusion surgery. Postoperative alterations in the adjacent segment biomechanics play a role in the etiology of these conditions. While experimental approaches fail to directly quantify spinal loads, previous modeling studies have numerous shortcomings when simulating the complex structures of the spine and the pre/postoperative mechanobiology of the patient. The biomechanical effects of the L4-L5 fusion surgery on muscle forces and adjacent segment kinetics (compression, shear, and moment) were investigated using a validated musculoskeletal model. The model was driven by in vivo kinematics for both preoperative (intact or severely degenerated L4-L5) and postoperative conditions while accounting for muscle atrophies. Results indicated marked changes in the kinetics of adjacent L3-L4 and L5-S1 segments (e.g., by up to 115% and 73% in shear loads and passive moments, respectively) that depended on the preoperative L4-L5 disc condition, postoperative lumbopelvic kinematics and, to a lesser extent, postoperative changes in the L4-L5 segmental lordosis and muscle injuries. Upper adjacent segment was more affected post-fusion than the lower one. While these findings identify risk factors for adjacent segment disorders, they indicate that surgical and postoperative rehabilitation interventions should focus on the preservation/restoration of patient’s normal segmental kinematics.