Multiple computational models have been developed to study knee biomechanics. However, the majority of these models are mainly validated against a limited range of loading conditions and/or do not include sufficient details of the critical anatomical structures within the joint. Due to the multifactorial dynamic nature of knee injuries, anatomic finite element (FE) models validated against multiple factors under a broad range of loading conditions are necessary. This study presents a validated FE model of the lower extremity with an anatomically accurate representation of the knee joint. The model was validated against tibiofemoral kinematics, ligaments strain/force, and articular cartilage pressure data measured directly from static, quasi-static, and dynamic cadaveric experiments. Strong correlations were observed between model predictions and experimental data (r > 0.8 and p < 0.0005 for all comparisons). FE predictions showed low deviations (root-mean-square (RMS) error) from average experimental data under all modes of static and quasi-static loading, falling within 2.5 deg of tibiofemoral rotation, 1% of anterior cruciate ligament (ACL) and medial collateral ligament (MCL) strains, 17 N of ACL load, and 1 mm of tibiofemoral center of pressure. Similarly, the FE model was able to accurately predict tibiofemoral kinematics and ACL and MCL strains during simulated bipedal landings (dynamic loading). In addition to minimal deviation from direct cadaveric measurements, all model predictions fell within 95% confidence intervals of the average experimental data. Agreement between model predictions and experimental data demonstrates the ability of the developed model to predict the kinematics of the human knee joint as well as the complex, nonuniform stress and strain fields that occur in biological soft tissue. Such a model will facilitate the in-depth understanding of a multitude of potential knee injury mechanisms with special emphasis on ACL injury.