Prolonged sitting, common in many workplaces, reduces blood flow to the lower limb and has negative health outcomes. CoreChair is an active-sitting chair that encourages increased movement to help mitigate these outcomes. Physiological and cognitive measures were recorded in ten subjects over 4 h of sitting in both the CoreChair and a traditional office chair. Sitting in both chairs led to increases in calf circumference (p < 0.0001), reduced tactile sensitivity (p = 0.02), and a cognitive decline in attention (p = 0.035) over time. However, the increase in calf circumference was smaller in the CoreChair at the second (p = 0.017) and third hour (p = 0.012) compared to the traditional chair. Additionally, for the attention task, the traditional chair generated more attention-task errors (p = 0.005), while no changes were observed with the CoreChair (p = 0.13). These findings suggest that during prolonged sitting CoreChair may have modest physiological and cognitive benefits compared to a traditional chair.