This research paper investigates the relationship between orchestration and harmony in Prokofiev’s orchestral works through selected case studies drawn from his symphonies and several of his symphonic suites. The research focuses on moments where the combination of orchestration and harmony stand out from the orchestral texture. Prokofiev uses these two elements of music to create both a large range of orchestral colors as well as to highlight structurally important moments in thematic development. Through the selected music examples, I highlight how the two elements are mutually dependent, even synergistic. I also argue that Prokofiev uses the two elements in a highly inventive manner to create unique timbral/harmonic effects. Drawing on recent theories related to timbre and perception, the chosen segments of music are analyzed in detail within the context of the works’ form and narrative. The study of these combinations suggests further research and interpretative possibilities for composers, music theorists, and performers.