U.S. global competitiveness in STI is supported through the nation’s investment and capabilities in STEM talent, R&D-driven discovery, and translation of knowledge into the economy and society through innovation. The data presented in this report show the evolving nature of the position of the United States in the global S&E landscape. The COVID-19 pandemic resulted in short-term disruptions to S&E education and research and led to substantial declines in the mathematics performance of American elementary and secondary mathematics students; otherwise, global levels of research and innovation have continued to increase. With respect to long-term trends, aggregate levels of S&E resources and activity have shifted toward East and Southeast Asia—in particular, China. The United States is the leading source of health sciences publications and patenting in chemistry and instruments, whereas China is the top producer of S&E doctoral degrees, total S&E publications, and international patents. The United States performs more total R&D than any other country and is by far the largest performer of basic research. However, the U.S. R&D system—and by extension, the nation’s competitiveness—relies heavily on foreign-born scientists and engineers, especially at the doctorate level. Rather than predominating across all elements of STI, the United States is distinguished by the strength of U.S. universities as destinations for international students, its highly cited and collaborative S&E research, and its global leadership in KTI services.