Enhanced sensitivity for the hepatotoxin microcystin-LR (MC-LR) was achieved in a quartz crystal microbalance (QCM) system via double amplification. For primary amplification, an innovative interface on the QCM was obtained as a matrix by the vesicle layer formed by our synthetic dendritic surfactant, bis (amidoethyl-carbamoylethyl) octadecylamine (C18N3). The vesicle matrix was then functionalised by an optimised concentration of monoclonal antibodies against MC-LR (anti-MC-LR) to detect the analyte. The results showed that a detection limit of 100ng/mL was achieved by primary amplification. To achieve higher sensitivity, secondary amplification was implemented with anti-MC-LR gold nanoparticle (AuNPs) conjugates as probes, which lowered the detection limit for MC-LR to 1ng/mL (the maximum concentration recommended by the World Health Organization [WHO] in drinking water for humans). The QCM immunosensor reported here has advantages such as high sensitivity, portability, simplicity, and cost-effectiveness for MC-LR detection. It would be uniquely superior compared with current MC-LR detection techniques for on-the-spot water detection. Furthermore, the methodology described here is also potentially significant in many fields for the routine monitoring of environmental and food safety.