Free radicals play an important role in cerebral ischemia-reperfusion injury. Accumulations of toxic free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) not only increase the susceptibility of brain tissue to ischemic damage but also trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and brain death. Activating matrix metalloproteinases (MMPs) is a key step in BBB disruption. MMPs are proteolytic zinc-containing enzymes responsible for degradation of the extracellular matrix around cerebral blood vessels and neurons. Free radicals can activate MMPs and subsequently induce the degradations of tight junctions (TJs), leading to BBB breakdown in cerebral ischemia-reperfusion injury. Recent studies revealed that caveolin-1, a membrane integral protein located at caveolae, can prevent the degradation of TJ proteins and protect the BBB integrity by inhibiting RNS production and MMPs activity. The interaction of caveolin-1 and RNS forms a positive feedback loop which provides amplified impacts on BBB dysfunction during cerebral ischemia-reperfusion injury. Here, we reviewed the recent progress in the interactions of RNS, caveolin-1 and MMPs. Current evidence indicates that the interactions of RNS, caveolin-1 and MMPs are critical signal pathways in BBB disruption and infarction enlargement during cerebral ischemia-reperfusion injury.