The liquid sampling atmospheric pressure glow discharge (LS-APGD) microplasma has shown promise in the fields of optical emission spectroscopy and mass spectrometry. In terms of mass spectrometry, it has allowed use of instruments normally applied in “organic” mass spectrometry, to be used for elemental/isotopic applications. The LS-APGD/Orbitrap combination is a particularly attractive alternative to traditional elemental MS systems due to its ability to perform ultra-high-resolution analyses, eliminating isobaric interferences which typically require extensive chemical separation prior to analysis. The LS-APGD has the ability to operate using four different powering modes; solution grounded cathode (SGC), solution grounded anode (SGA), solution powered cathode (SPC), and solution powered anode (SPA). To investigate the utility of each powering mode, the elemental responses and isotope ratio performance were assessed for the pertinent operating parameters (discharge current, solution flow rate, gas flow rate, and inter-electrode displacement). Experiments were performed using a 500 ng mL−1 multielement solution containing Rb, Ag, Ba, Tl, and U. Measurements of 235U/238U were performed using a 200 ng mL−1 solution of CRM-129a. Ultimately, it was determined that the SGC mode showed the best performance in terms of elemental intensity, accuracy, and precision for isotope ratio measurements. The optimal electrode configuration consists of the solution electrode in line with the ion-sampling orifice of the MS, with the counter electrode oriented perpendicular to that axis.