Layered silicates (LS, clays) are a composite group of minerals whose industrial interest and technological applications are progressively expanding, spanning from catalysis to biomedicine. However, the compatibility of LS with biological systems is not clear, and mechanistic data about biophysicochemical interactions at the interface of LS and biomembranes are scarce. Here, cell membrane damage, assessed using red blood cells as model membranes, is revealed for kaolin (> 75 wt.% kaolinite, 1:1 layer structure) and bentonite (> 90 wt.% montmorillonite, 1:2 layer structure) particles. The high membranolytic capacity of bentonite (i.e., high ion‐exchanger LS) is the result of the combined contribution of both mineral surface features and sample‐specific cation exchange capacity (CEC). For kaolin (i.e., non‐ion‐exchanger LS), the capacity to damage membranes is primarily due to surface hydroxyl species, that is, silanols and aluminols, exposed at the crystal lattice boundaries. When kaolin is thermally disorganized into amorphous metakaolin, membrane damage is driven by a specific sub‐population of surface hydroxyl species, namely the “nearly free silanols”, previously evidenced on quartz. This study establishes the rationale underlying the interactions between LS particles and membranes and can set the basis for the understanding of interfacial phenomena of LS.