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Abstract Cells transmit piconewton forces to receptors to mediate processes such as migration and immune recognition. A major challenge in quantifying such forces is the sparsity of cell mechanical events. Accordingly, molecular tension is typically quantified with high resolution fluorescence microscopy, which hinders widespread adoption and application. Here, we report a mechanically triggered hybridization chain reaction (mechano‐HCR) that allows chemical amplification of mechanical events. The amplification is triggered when a cell receptor mechanically denatures a duplex revealing a cryptic initiator to activate the HCR reaction in situ. Importantly, mechano‐HCR enables direct readout of pN forces using a plate reader. We leverage this capability and measured mechano‐IC₅₀for aspirin, Y‐27632, and eptifibatide. Given that cell mechanical phenotypes are of clinical importance, mechano‐HCR may offer a convenient route for drug discovery, personalized medicine, and disease diagnosis.