An investigation of the deactivation of pathogens using electromagnetic waves in the microwave region of the spectrum is achieved using custom-built waveguide structures. The waveguides feature sub-wavelength gratings to allow the integration of an air cooling system without disturbing the internal propagating fields. The waveguides are tapered to accommodate an experimental sample internally with sufficient surrounding airflow. The proposed methodology allows for precise control over power densities due to the well-defined fundamental mode excited in each waveguide, in addition to temperature control of the sample due to microwave exposure over time. Human coronavirus (HCoV-229E) is investigated over the 0–40 GHz range, where a peak 3-log viral reduction is observed in the 15.0–19.5 GHz sub-band. We conclude HCoV-229E has an intrinsic resonance in this range, where nonthermal structure damage is optimal through the structure-resonant energy transfer effect.