Highly efficient, long-term, eco-friendly catalysts for water decontamination technology are urgently needed to meet the prioritized objectives of green development and societies worldwide. Ca-doped ZnO was investigated as environmentally friendly sono-photocatalytic system under LED visible light irradiation to efficiently mineralize tetracycline-based antibiotics. The effects of pH, Ca doping, light, ultrasound, and pH on the mineralization of tetracycline by Ca-doped ZnO nanopowders and on the chemical, sono-, photo- and sono-photostability of Ca-doped ZnO nanopowders were systematically investigated. The ZnO-based catalyst with 2 at. % of Ca dopant exhibited the best sono-photocatalytic performance in mineralizing tetracyclines under visible LED light and ultrasound irradiation (i.e., ≥99% mineralization in 90 min), with excellent reusability and minimal sono-photocorrosion (i.e., ≤1% of catalyst dissolution in 180 min), which were even greater in the absence of organic pollutants and in the pH range of most natural waters. For Ca-doped ZnO nanopowders, the role of the generated reactive oxygen species under light and ultrasound stimulation and the mechanism of the mineralization of tetracycline were analyzed. In conclusion, the sono-photocatalytic mineralization of antibiotics synergizing visible LED light and weak ultrasound irradiation in the presence of Ca-doped ZnO nanopowders presents an outstanding start to developing highly efficient, long-term, eco-friendly catalysts for efficiently treating emerging organic pollutants.