The electro-peroxone (EP) process encounters two inherent challenges in wastewater treatment: sluggish O2/O3 transfer and substantial ozone waste. To overcome these limitations, we introduced micro-nano bubbles (MNBs) aeration to enhance O2/O3 dissolution and diffusion, ultimately aiming to improve the removal of trace pharmaceutical contaminants from hospital wastewater. In the MNBs aeration system, the ozone transfer coefficient ranging from 0.536 to 0.265 min−1, significantly surpassing that of conventional aeration (0.220 to 0.090 min−1) by approximately 2 to 4.5 times. Consequently, the EP process under MNBs aeration significantly enhanced ozone-resistant ibuprofen (IBU) removal, achieving a removal rate of 98.4 ± 1.5 %, far exceeding the 47.3 ± 4.7 % observed with conventional aeration. This significant improvement was attributed to the heightened production of hydroxyl radicals (•OH), reaching 0.97 × 10−9 M s, compared to only 0.28 × 10−9 M s in conventional aeration. The mechanism behind the enhanced •OH production in the MNBs-EP process relied primarily on two factors: improved O2/O3 dissolution due to high internal pressure/large surface and enhanced O3/H2O2 activation from high collapse energy. These factors together contributed to the robust oxidation capability of the MNBs-EP system. As a result, over 97 % removal efficiency was achieved for five representative pharmaceutical pollutants (sulfamethoxazole, ribavirin, norfloxacin, tetracycline and ampicillin) in just 1 min. Furthermore, when applied to real hospital wastewater, the MNBs-O3-E treatment system reduced all 15 detected trace pharmaceutical compounds to below 10 ng L−1 and achieved 14 types of pollutants with removal rates of over 85 % within 15 min, resulting in an ultrahigh total removal rate of 98.6 %, from an initial total concentration of 2108 ng L−1 to less than 30 ng L−1. Thus, micro-nano aeration endowed the EP process as a promising advanced oxidation system for rapid and highly-effective removal of trace pharmaceutical contaminants from hospital wastewater.