<p>The utilization efficiency (UE) of ozone plays a decisive role in the operating cost of wastewater ozonation. However, it remains obscure which engineering factors (including reactor design parameters and operating conditions) actually govern the UE of ozone, especially during practical wastewater treatment and in scaled-up reactors. Herein, we proposed the definitions of generalized UE (GUE) and narrowly-defined UE (NUE) with emphasis on the overall ozone consumption and the specific utilization of ozone in chemical oxygen demand removal, respectively, and thereby methodically evaluated the effects of various engineering factors on GUE and NUE of ozone during wastewater ozonation in bubble column reactors from bench to pilot scales. Single factor analysis shows that increasing superficial gas velocity (<i>U</i>_sg, i.e., normalized gas flow rate) significantly inhibits both GUE and NUE, while the increase of mass transfer height (<i>h</i>) and column diameter promotes GUE, whereas it has no significant effect on NUE. Increasing gaseous ozone concentration exhibits a negligible impact on GUE but an adverse influence on NUE. Furthermore, the joint effects of every two factors on GUE and NUE were elucidated through response surface methodology analysis, wherein GUE was found to be effectively modulated via adjusting <i>h</i> and <i>U</i>_sg under a binary restriction condition of <i>h</i> &lt; 1875<i>U</i>_sg. More importantly, a series of multi-factor regression models were successfully established to predict the NUE of ozone at bench scale and for GUE across bench and pilot scales, respectively. This study is of techno-economic significance in promoting ozone utilization for efficient wastewater treatment via illuminating the rational design of the bubble column reactor and operating conditions.</p>