AbstractOpen-shell nanographenes appear as promising candidates for future applications in spintronics and quantum technologies. A critical aspect to realize this potential is to design and control the magnetic exchange. Here, we reveal the effects of frontier orbital symmetries on the magnetic coupling in diradical nanographenes through scanning probe microscope measurements and different levels of theoretical calculations. In these open-shell nanographenes, the exchange energy exhibits a remarkable variation between 20 and 160 meV. Theoretical calculations reveal that frontier orbital symmetries play a key role in affecting the magnetic coupling on such a large scale. Moreover, a triradical nanographene is demonstrated for investigating the magnetic interaction among three unpaired electrons with unequal magnetic exchange, in agreement with Heisenberg spin model calculations. Our results provide insights into both theoretical design and experimental realization of nanographene materials with different exchange interactions through tuning the orbital symmetry, potentially useful for realizing magnetically operable graphene-based nanomaterials.