In 1980, the area protected by the sanctuary system grew exponentially as the nearly 1500-square-mile Channel Islands National Marine Sanctuary was designated to protect the islands in the Santa Barbara Channel, as one of the last areas in California regarded as relatively untouched by human activity. This site was the first "modern" ecosystem-based sanctuary and the model for NOAA's future sanctuaries. The comprehensive yet practical management approach is used to promote long-term conservation of sanctuary waters, wildlife, habitats, and cultural resources, while allowing compatible human uses.

The sanctuary would go on to provide unprecedented protection to the resources of the Channel, including supporting the 1991 establishment of an Area to Be Avoided surrounding the sanctuary (the first in the sanctuary system), completing an extensive network of marine reserves, and pioneering a call for action about ocean acidification through the Sanctuary Advisory Council, after which 12 other advisory councils followed suit.