Tire inflation pressure affects both tire longitudinal and lateral stiffness and thus may impose a considerable influence on vehicle dynamics and handling performance. This paper presents a comprehensive study revealing the effects of tire pressure variations and their distribution among four tires on vehicle dynamics and handling performance. An extended Magic Formula tire model and a modified UniTire model involving tire inflation pressure are employed to describe the tire longitudinal and lateral forces, respectively. Two groups of vehicle maneuvers are simulated in CarSim: a single lane change maneuver with braking and a double lane change maneuver, to exhibit the effects of tire inflation pressure. Various tire pressure variations including all four tires at same and different pressures are examined. A vehicle dynamics, lateral motion stability index, and driver steering workload are utilized to quantify the influence of tire pressure variations and distributions. Analyses on the simulation results indicate that: 1) a front tire pressure reduction induces vehicle understeering tendency and a larger steering angle; 2) a rear tire pressure reduction causes oversteering characteristics and a sacrifice on vehicle stability with a larger vehicle sideslip angle; 3) all-tire inflation pressure decrease will increase driver’s steering workload; and 4) lower rear-tire inflation pressure can promote the combined performance of vehicle path-tracking and driver’s steering workload.