By treating heavy oil as multiple pseudocomponents, techniques have been developed to experimentally and theoretically determine diffusion coefficients of CO2-heavy oil systems by coupling heat and mass transfer together with consideration of swelling effect. Experimentally, diffusion tests have been conducted for hot CO2-heavy oil systems with three different temperatures under a constant pressure by using a visualized pressure-volume-temperature (PVT) setup. The swelling of liquid phase in the PVT cell is continuously monitored and recorded during the measurements. Theoretically, a two-dimensional (2D) mathematical model incorporating the volume-translated Peng–Robinson equation of state (PR EOS) with a modified alpha function has been developed to describe heat and mass transfer for hot CO2-heavy oil systems. Heavy oil sample has been characterized as three pseudocomponents for accurately quantifying phase behavior of the CO2-heavy oil systems, while the binary interaction parameters (BIPs) are tuned with the experimentally measured saturation pressures. The diffusion coefficient of hot CO2 in heavy oil is then determined once the discrepancy between the experimentally measured dynamic swelling factors and theoretically calculated ones has been minimized. During the diffusion experiments, heat transfer is found to be dominant over mass transfer at the beginning and reach its equilibrium in a shorter time; subsequently, mass transfer shows its dominant effect. The enhanced oil swelling mainly occurs during the coupled heat and mass transfer stage. CO2 diffusion coefficient in heavy oil is found to increase with temperature at a given pressure, while it can be explicitly correlated as a function of temperature.