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Oxidative stress is one of the hallmarks of ischemic stroke. Catalase-based (CAT) biomimetic complexes are emerging as promising therapeutic candidates that are expected to act as neuroprotectants for ischemic stroke by decreasing the damaging effects from H 2 O 2 . Unfortunately, these molecules result in the unwanted production of the harmful hydroxyl radical, HO • . Here, we report a series of salen-based tri-manganese (Mn(III)) metallocryptands ( 1 - 3 ) that function as catalase biomimetics. These cage-like molecules contain a unique "active site" with three Mn centers in close proximity, an arrangement designed to facilitate metal cooperativity for the effective dismutation of H 2 O 2 with minimal HO • production. In fact, significantly greater oxygen production is seen for 1 - 3 as compared to the monomeric Mn(Salen) complex, 1c . The most promising system, 1 , was studied in further detail and found to confer a greater therapeutic benefit both in vitro and in vivo than the monomeric control system, 1c , as evident from inter alia studies involving a rat model of ischemic stroke damage and supporting histological analyses. We thus believe that metallocryptand 1 and its analogues represent a new and seemingly promising strategy for treating oxidative stress related disorders.