The Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission is currently operating in proximity to the near-Earth asteroid (NEA) Bennu. OSIRIS-REx is scheduled to perform a Touch and Go (TAG) sample acquisition in the fall of 2020 and then return the sample to Earth. This paper details the design and optimization of the Earth-return trajectory. Daily departure trajectories for several months surrounding the baseline departure date of March 3, 2021 are presented, along with the results of trade studies examining departure dates through September 2022. The capabilities of the trajectory optimization engine used in this work—NASA Goddard Space Flight Center’s (GSFC) Evolutionary Mission Trajectory Generator (EMTG)—are also described, with an emphasis on newer features that enable EMTG to optimize the OSIRIS-REx Earth-return trajectory.