The aim of the present investigation was the combination of ZnO nanostructures with nano-cellulose (NC) for the efficient degradation of tetracycline (TC) antibiotic under ultrasonic irradiation. The removal efficiency of 12.8% was obtained by the sole use of ultrasound (US), while the removal efficiency increased up to 70% by the US/ZnO treatment process. Due to the integration of ZnO nanostructures with NC, the removal efficiency of 87.6% was obtained within 45 min. The removal efficiency substantially decreased in the presence of tert-butyl alcohol (more than 25% reduction), indicating that radOH-mediation oxidation is responsible for the degradation of TC molecules. Peroxymonosulfate (PMS) led to the most enhancing effect on the removal of TC among percarbonate, persulfate and periodate ions. The addition of PMS caused the degradation efficiency of 96.4% within the short contact time of 15 min. The bio-toxicity examination on the basis of inhibition test conducted on activated sludge revealed diminishing the oxygen consumption inhibition percent [IOUR (%)] from 33.6 to 22.1% during the US/ZnO/NC process. Consequently, the utilization of the US/ZnO/NC process can convert TC molecules to less toxic compounds. However, longer reaction time is required for complete conversion into non-toxic substances.