A wide range of fundamental cellular activities rely on lipid membrane fusion. Membrane fusion processes can be mimicked by synthetic approaches to understand fusion mechanisms and develop novel drug delivery systems and therapeutic agents. Recently, membrane-embedded amphiphilic gold nanoparticles (AuNPs) have been employed as artificial fusogens to induce finely tuned membrane fusion in vitro. However, the physical determinants driving and regulating the fusion process mediated by AuNPs remain largely unexplored, thus limiting the application potential of this synthetic fusion system. Herein, we focus on unraveling the effect of the interplay between the curvature of the lipid membrane and the size of amphiphilic AuNPs during fusion events. We employed AuNPs with the same surface chemistry but different core diameters (similar to 2 nm and similar to 4 nm) interacting with phosphatidylcholine unilamellar vesicles of different membrane curvatures containing a biologically relevant percentage of cholesterol. Based on a combination of fluorescence spectroscopy assays, dissipative quartz microbalance, and molecular dynamics simulations, our findings reveal that small AuNPs promote vesicle fusion regardless of the membrane curvature. In contrast, large AuNPs do not exhibit fusogenic properties with low curvature membranes and can induce fusion events only with significantly curved membranes. Large NPs impede the progression from the stalk state to the hemifused state via steric hindrance, an effect that is only partially compensated by the membrane curvature. These results offer novel insights into the role of AuNP core size and membrane curvature in mediating the interaction between the vesicles during fusion and highlight how understanding these physical determinants has broad implications in fully exploiting the application potential of novel synthetic fusion approaches.