The sodium leak channel NALCN (Na+ leak channel, non-selective) is expressed throughout numerous mammalian tissues, especially in neurons. It has been identified as a major contributor to background sodium conductance, and hence resting membrane potential and cellular excitability. Unsurprisingly, the extent of NALCN activity is highly regulated in most cell types. Specifically, several G protein-coupled receptors (GPCRs) have been shown to regulate NALCN, both in cell lines and native tissues. The mechanism behind this functional regulation, however, remains poorly understood. Here, we investigate the regulation of NALCN by GPCRs and the underlying signaling pathways by expressing the NALCN channel complex (including NALCN, UNC79, UNC80, and FAM155A) in Xenopus laevis oocytes together with several different GPCRs and G protein subunits, while evaluating NALCN function using two-electrode voltage-clamp (TEVC). We find that activation of the GABA-B receptor (GABA-BR) co-expressed with NALCN leads to a small, but consistent and reversible reduction in NALCN currents. We propose this effect to be mediated by the GABA-BR-coupled G αi subunit, because co-expression of it alone, but not G β1γ2, leads to a significant inhibition of NALCN currents. Using mutants that lock G αi in either its active or inactive state, we find that the active state of G αi tends to inhibit NALCN more strongly, while inactive G αi mutants show less pronounced inhibition. However, pharmacological inhibition of the adenylyl cyclase, the main downstream target of G αi, does not lead to a reduction in NALCN currents, possibly suggesting a direct interaction between the G protein and the NALCN sodium leak channel complex. Overall, our data demonstrate that GPCRs and G protein αi in particular can regulate NALCN function. However, the underlying mechanisms for these observations remain to be elucidated.