Histamine is a ubiquitous autocoid that mediates a vast variety of physiological processes through the binding to one of its four G-protein coupled receptors (H₁R, H₂R, H₃R and H₄R). Using patch-clamp electrophysiology in conventional whole-cell mode, and calcium (Ca²⁺) imaging we found that histamine induced powerful conductance that was associated with augmented intracellular Ca²⁺ in human retinal glial Müller cells MIO-M1. Inhibition of the histamine effects with H1R antagonist and phospholipase C inhibitor U73122 unveiled the signal transduction through G_q/11 cascade. Suppression of intracellular Ca²⁺ signal and transmembrane current with xestospongin C confirmed further involvement of Ca²⁺ release from endoplasmic reticulum (ER) through inositol triphosphate receptors (IP₃R), and passive depletion of ER stores with reticular Ca²⁺ adenosine triphosphatase (Ca²⁺ ATPase)  inhibitor cyclopiazonic acid (CPA) and Ca²⁺ chelator 1,2-Bis 2-aminophenoxy ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM) verified store-dependence of the histamine signalling in human retinal glial Müller cells MIO-M1. Sensitivity of the histamine signals with nominal Ca²⁺ free solution and NiCl₂ highlighted importance of the extracellular Ca²⁺ influx, that was confirmed with 2APB the inhibitor of transient receptor potential (TRP) channels, presumably melastatin (TRPM) subfamily. The expression of H₁R, TRPM7 and glial markers was confirmed using immunocytochemistry. Taken together, this study establishes a novel H₁R/TRPM7 mechanism that in human retinal glial Müller cells might play important role in retinopathies such as fluid accumulation in macular oedema and neovasculisation in diabetic retinopathy.