The removal of caffeine (CAF) in aqueous solution by peroxymonosulfate oxidant activated with cobalt ion was investigated under a variety of operating conditions. The effects of various operating parameters, such as oxone and Co2+ concentrations, pH value, and the coexistence of dissolved organic matter and inorganic anions on the removal of CAF have been investigated. The removal efficiency increased with the increase in the concentrations of oxone and Co2+ ion added. The additions of chloride, bicarbonate, and sodium humate have negative effects on the removal of CAF. Near-neutral condition (5.0 < pH < 7.0) is favorable for the removal of CAF. Based on our experiments, 100% degradation of 50 mg/L CAF can be achieved within 4 minutes under the conditions of 1.00 mM oxone and 0.10 mM Co2+ ion at pH 5.0–7.0.