Ghrelin is a gut hormone that enhances food intake and growth hormone secretion through its receptor, the G-protein coupled receptor (GPCR) GHSR1a. Recently, we showed that ghrelin interacts with syndecans (SDCs), a family of membrane proteins that have been linked to obesity in genome-wide association studies. Here, we investigated whether SDCs impact ghrelin signalling at GHSR1a. We used HEK293 cells that expressed GHSR1a and SDC1, SDC2, SDC3, or SDC4 through transient transfection. GHSR1a mainly signals through the Gα_q pathway, so we first explored the effects of syndecans on ghrelin-induced intracellular Ca²⁺ influx. We found that all SDCs increased maximum Ca²⁺ response at least 4.2-fold (P<0.001), without affecting the EC₅₀ of the response. Transfection of the cells with SDC1 alone did not permit a ghrelin-stimulated Ca²⁺ response, showing that the mechanism of action is GHSR1a-dependent. The SDC-potentiated response is also Gα_q-dependent, since no Ca²⁺ response was observed in GNAQ knock-out cells transfected with GHSR1a and SDC1 expression plasmids. The enhanced Ca²⁺ response was not caused by increased receptor availability: SDCs reduced cell membrane receptor expression by 51-85% (P<0.001). Nonetheless, ghrelin-stimulated Gα_q activation was similar in cells with and without SDCs. β-arrestins function as scaffolding proteins, that downregulate GPCR function following activation by sterically hindering G-protein coupling and mediating receptor internalisation. Therefore, we thought the enhanced Ca²⁺ signalling could be caused by reduced quenching of GHSR1a function by β-arrestins. Indeed, we found that SDCs nearly completely blunted β-arrestin 2 recruitment to GHSR (P<0.001). It remains to be determined if this directly potentiates ghrelin-induced GHSR1a signalling, or whether it is an independent effect of SDC co-expression. Altogether, we showed that SDCs enhance the Ca²⁺ response of GHSR1a to ghrelin, potentially by reducing β-arrestin 2 recruitment. This could be a novel mechanism through which SDCs affect metabolism and obesity.