Marine Spatial Planning (MSP) provides a process that uses spatial data and models to evaluate environmental, social, economic, cultural, and management trade-offs when siting (i.e., strategically locating) ocean industries. Aquaculture is the fastest-growing food sector in the world. The United States (U.S.) has substantial opportunity for offshore aquaculture development given the size of its exclusive economic zone, habitat diversity, and variety of candidate species for cultivation. However, promising aquaculture areas overlap many protected species habitats. Aquaculture siting surveys, construction, operations, and decommissioning can alter protected species habitat and behavior. Additionally, aquaculture-associated vessel activity, underwater noise, and physical interactions between protected species and farms can increase the risk of injury and mortality. In 2020, the U.S. Gulf of Mexico was identified as one of the first regions to be evaluated for offshore aquaculture opportunities as directed by a Presidential Executive Order. We developed a transparent and repeatable method to identify aquaculture opportunity areas (AOAs) with the least conflict with protected species. First, we developed a generalized scoring approach for protected species that captures their vulnerability to adverse effects from anthropogenic activities using conservation status and demographic information. Next, we applied this approach to data layers for eight species listed under the Endangered Species Act, including five species of sea turtles, Rice’s whale, smalltooth sawfish, and giant manta ray. Next, we evaluated four methods for mathematically combining scores (i.e., Arithmetic mean, Geometric mean, Product, Lowest Scoring layer) to generate a combined protected species data layer. The Product approach provided the most logical ordering of, and the greatest contrast in, site suitability scores. Finally, we integrated the combined protected species data layer into a multi-criteria decision-making modeling framework for MSP. This process identified AOAs with reduced potential for protected species conflict. These modeling methods are transferable to other regions, to other sensitive or protected species, and for spatial planning for other ocean-uses.