The neuropeptide VGF was recently proposed as a neurodegeneration biomarker. The Parkinson’s disease-related protein leucine-rich repeat kinase 2 (LRRK2) regulates endolysosomal dynamics, a process that involves SNARE-mediated membrane fusion and could regulate secretion. Here we investigate potential biochemical and functional links between LRRK2 and v-SNAREs. We find that LRRK2 directly interacts with the v-SNAREs VAMP4 and VAMP7. Secretomics reveals VGF secretory defects in VAMP4 and VAMP7 knockout (KO) neuronal cells. In contrast, VAMP2 KO “regulated secretion-null” and ATG5 KO “autophagy-null” cells release more VGF. VGF is partially associated with extracellular vesicles and LAMP1+ endolysosomes. LRRK2 expression increases VGF perinuclear localization and impairs its secretion. Retention using selective hooks (RUSH) assays show that a pool of VGF traffics through VAMP4+ and VAMP7+ compartments, and LRRK2 expression delays its transport to the cell periphery. Overexpression of LRRK2 or VAMP7-longin domain impairs VGF peripheral localization in primary cultured neurons. Altogether, our results suggest that LRRK2 might regulate VGF secretion via interaction with VAMP4 and VAMP7. Display omitted •LRRK2 interacts with the endosomal v-SNAREs VAMP4 and VAMP7•VAMP4 and VAMP7 mediate the secretion of the Parkinson’s disease biomarker VGF•LRRK2 regulates the accumulation vs. secretion of VGF Filippini et al. report the direct interaction of leucine-rich repeat kinase 2 (LRRK2) with the endosomal vesicular SNAREs VAMP4 and VAMP7. LRRK2, VAMP4, and VAMP7 regulate the secretion of the Parkinson’s disease biomarker VGF. They provide evidence for the role of LRRK2 in regulating unconventional secretion in the disease.