Non-invasive, continuous measurements in vivo are commonly used to make inferences about mechanisms controlling internal and external respiration during exercise. In particular, the dynamic response of muscle oxygenation (StO_2m) measured by near-infrared spectroscopy (NIRS) is assumed to be correlated to that of venous oxygen saturation (StO_2v) measured invasively. However, there are situations where the dynamics of StO_2m and StO_2v do not follow the same pattern. A quantitative analysis of venous and muscle oxygenation dynamics during exercise is necessary to explain the links between different patterns observed experimentally. For this purpose, a mathematical model of oxygen transport and utilization that accounts for the relative contribution of Hb and Mb to the NIRS signal was developed. This model includes changes in microvascular composition within skeletal muscle during exercise and integrates experimental data in a consistent and mechanistic manner. Three subjects (age 25.6±0.6 yr) performed square-wave moderate exercise on a cycle-ergometer under normoxic and hypoxic conditions, while muscle oxy- and de-oxygenation (C_oxy, C_deoxy) were measured by NIRS. Under normoxia, the oxygenated Hb/Mb concentration (C_oxy) drops rapidly at the onset of exercise and then increases monotonically. Under hypoxia, C_oxy decreases exponentially to a steady state within ~2 min. In contrast, model simulations of venous oxygen concentration (C_ven) show an exponential decrease under both conditions due to the imbalance between oxygen delivery and consumption at the onset of exercise. Also, model simulations that distinguish the dynamic responses of oxy/de-oxygenated Hb (HbO₂, HHb) and Mb (MbO₂, HMb) concentrations (C_oxy=HbO₂+MbO₂; C_deoxy=HHb+HMb) show that both Hb and Mb contribution to the NIRS signal are comparable. Analysis of NIRS signal components during exercise with mechanistic model of oxygen transport and metabolism indicates that changes in oxygenated Hb and Mb are responsible of different patterns of StO_2m and StO_2v dynamics observed under normoxia and hypoxia.