Microwave resonators working as sensors can detect only a single analyte at a time. To address this issue, a TE20-mode substrate-integrated waveguide (SIW) resonator is exploited, owing to its two distinct regions of high-intensity electric fields, which can be manipulated by loading two chemicals. Two microfluidic channels with unequal fluid-carrying capacities, engraved in a polydimethylsiloxane (PDMS) sheet, can perturb the symmetric electric fields even if loaded with the two extreme cases of dielectric [ethanol (E), deionized water (DI)] and [deionized water, ethanol]. The four layers of the sandwiched structure considered in this study consisted of a top conductive pattern and a bottom ground, both realized on a Rogers RT/Duroid 5880. PDMS-based channels attached with an adhesive serve as the middle layers. The TE20-mode SIW with empty channels resonates at 8.26 GHz and exhibits a −25 dB return loss with an unloaded quality factor of Q ≈ 28. We simultaneously load E and DI and demonstrate the detection of the four possible combinations: [E, DI], [DI, E], [E, E], and [DI, DI]. The performance of our proposed method showed increases in sensitivity (MHz/εr) of 7.5%, 216%, and 1170% compared with three previously existing multichannel microwave chemical sensors.