Increased worldwide consumption of antiviral drugs (AVDs) amid COVID-19 has induced enormous burdens to the existing wastewater treatment systems. Microalgae-based bioremediation is a competitive alternative technology due to its simultaneous nutrient recovery and sustainable biomass production. However, knowledge about the fate, distribution, and interaction of AVDs with microalgae is yet to be determined. In this study, a concentration-determined influence of AVD oseltamivir (OT) was observed on the biochemical pathway of Chlorella sorkiniana (C.S-N1) in synthetic municipal wastewater. The results showed that high OT concentration inhibited biomass growth through increased oxidative stress and restrained photosynthesis. Nevertheless, complete OT removal was achieved at its optimized concentration of 10 mg/L by various biotic (82%) and abiotic processes (18.0%). The chemical alterations in three subtypes of extracellular polymeric substances (EPS) were primarily investigated by electrostatic (OT +8.22 mV vs. C.S-N1 -18.31 mV) and hydrophobic interactions between EPS-OT complexes supported by secondary structure protein analysis. Besides, six biodegradation-catalyzed transformation products were identified by quadrupole-time-of-flight mass spectrometer and by density functional theory. Moreover, all the TPs exhibited log Kow ≤ 5 and bioconcentration factor values of < 5000 L/kg, meeting the practical demands of environmental sustainability. This study broadens our understanding of microalgal bioadsorption and biodegradation, promoting microalgae bioremediation for nutrient recovery and AVDs removal.