A facile one-pot spray-drying process was developed for fabrication and in situ crosslinking of chitosan microspheres to improve the adsorption capacity by microscopic design. A fully biobased nature was achieved by utilizing genipin (GP) as a crosslinking agent and chitosan-derived nanographene oxide (nGO) as a property tuner. The produced chitosan microspheres were further proven as powerful adsorbents for common wastewater contaminants such as anionic dyes and pharmaceutical contaminants, here modeled by methyl orange (MO) and diclofenac sodium (DCF). By regulating the amount of GP and nGO, as well as by controlling the process parameters including the spray-drying inlet temperature and postheat treatment, the surface morphology, size, zeta potential, and adsorption efficiency of the microspheres could be tuned accordingly. The adsorption efficiency for MO and DCF reached 98.9 and 100%, respectively. The microspheres retained high DCF adsorption efficiency after six adsorption and desorption cycles, and the recyclability was improved by the incorporated nGO. The fabricated microspheres, thus, have great potential as reusable and eco-friendly adsorbents.