The blood brain barrier (BBB) is the network of capillaries that controls the passage of substances from the blood into the brain and other parts of the central nervous system (CNS). As this barrier is the major obstacle for drug delivery into CNS, a credible BBB model is very necessary to assess the BBB permeability of novel neuroactive compounds including thousands of bioactive compounds which have been extracted from medicinal plants and have the potential for the treatment of CNS diseases. Increasing reports indicated that zebrafish has emerged as a timely, reproducible model for BBB permeability assessment. In this review, the development and functions of the BBB in zebrafish, such as its anatomical morphology, tight junctions, drug transporters and enzyme expression, are compared with those in mammals. The studies outlined in this review describe the utilization of the zebrafish as a BBB model to investigate the permeability and distribution of fluorescent dyes and drugs. Particularly, this review focuses on the use of zebrafish to evaluate the delivery of natural products and nanosized drug delivery systems across the BBB. Due to the highly conserved nature of both the structure and function of the BBB between zebrafish and mammals, zebrafish has the potential to be developed as a model for assessing and predicting the permeability of BBB to novel compounds.