Ecosystem-based fisheries management (EBFM) and ecosystem restoration are gaining momentum worldwide, including in U.S. waters of the Gulf of Mexico (GOM). Ecosystem models are valuable tools for informing EBFM and restoration activities. In this paper, we provide guidance and a roadmap for ecosystem modeling in the GOM region, with an emphasis on model development and use of model products to inform EBFM and the increasing investments in restoration. We propose eight “best practices” for ecosystem modeling efforts, including (1) identification of priority management questions, (2) scenarios as simulation experiments, (3) calibration and validation needs, (4) sensitivity and uncertainty analyses, (5) ensuring transparency, (6) improving communication between ecosystem modelers and the various stakeholders, (7) documentation of modeling efforts, and (8) maintaining the ecosystem models and codes. Fisheries management in the USA adheres to a prescriptive set of calculations. Therefore, the use of ecosystem modeling in EBFM for the GOM will likely be incremental, starting with the incorporation of environmental variables into single-species assessments, the provision of background (stage-setting) information on environmental and food web effects (e.g., the impacts of lionfish Pterois spp. invasion), and strategic advice through management strategy evaluation. Management questions related to restoration in the GOM (e.g., the impacts of freshwater and sediment diversions as part of coastal restoration, habitat preservation, and rehabilitation; and measures to mitigate nutrient loading and hypoxia) have more flexibility in how they are addressed and thus are primed for immediate use of ecosystem modeling. The questions related to restoration are appropriate for ecosystem modeling, and data collection at the restoration project level can provide critical information for modeling to then scale up to regional responses. Ecosystem modeling efforts need to be initiated and advanced now in order for the tools to be ready in the near future. Addressing resource management issues and questions will benefit greatly from the proper use of ecosystem modeling.