The marine dinoflagellate Cochlodinium polykrikoides is a harmful algal bloom (HAB) species that severely impacts the environment and causes huge economic losses. Yellow clay (YC), considered to be a non-toxic and naturally-occurring material, represents an important step towards the direct control of HABs. In the present study, we evaluated the physiological and biochemical effects of YC on C. polykrikoides after exposures of up to 72 h. We observed little physiological changes in growth rate, chlorophyll a, lipid peroxidation, antioxidant enzymatic activities of superoxide dismutase and catalase, and activity of alkaline phosphatase after exposure to YC. Interestingly, YC significantly increased total carbohydrate and glutathione levels, affecting the physiology of the cells. These results indicate that total carbohydrate content may play an important role in cell-clay aggregation and it could be the main underlying mechanism that mitigates HAB cells via sedimentation.