Mathematics and computational methods are of fundamental importance in the design and analysis of nuclear systems. The “Math & Comp” research community is actively engaged in advancing numerical algorithms and computational methods to simulate nuclear systems with increasingly higher fidelity. The American Nuclear Society (ANS) 2021 International Conference on Mathematics and Computational Methods Applied to Nuclear Science and Engineering (M&C 2021) continued the rich tradition of this biennial conference series, showcasing preeminent computational science research for nuclear applications. M&C 2021 was an M&C conference like none before. Much of the planning for the conference was conducted amid the uncertainty of the COVID-19 pandemic via e-mail and Zoom sessions in 2020 and 2021. The conference was originally scheduled for April 11–15, 2021, in Raleigh, North Carolina. The pandemic resulted in the delay of the conference to October 3–7, 2021, and the COVID-19 Delta surge led to the last-minute decision to go fully virtual for the first time in the history of the conference. A constant focus in planning the conference was a strong commitment to excellence in the technical program, a hallmark of this series of conferences. The papers in this special issue of Nuclear Science and Engineering represent selected highlights of the research presented at M&C 2021. The themes of M&C 2021 were mathematical and computational methods, numerical analysis, computer codes, and high-performance computer architectures for solving problems in nuclear science and engineering. The M&C 2021 technical program was based on 14 technical tracks: