We demonstrate sodium pyruvate (NaPy) pre‐treatment as a successful approach for pressure ulcer (PU) prevention by averting their aetiological origin—cell‐level damage and death by large, sustained mechanical loads. We evaluated the NaPy pre‐treatment effect on permeability changes in the cell's plasma membrane (PM) following application of in vitro damaging‐level strains. Fibroblasts or myoblasts, respectively, models for superficial or deep‐tissue damage were grown in 0 or 1 mM NaPy, emulating typical physiological or cell culture conditions. Cells were pre‐treated for 4 hours with 0 to 5 mM NaPy prior to 3‐hour sustained, damaging‐level loads (12% strain). PM permeability was quantified by the cell uptake of small (4 kDa), fluorescent dextran compared with unstrained control using fluorescence‐activated cell sorting (FACS). Pre‐treatment with 1 mM, and especially 5 mM, NaPy significantly reduces damage to PM integrity. Long‐term NaPy pre‐exposure can improve protective treatment, affecting fibroblasts and myoblasts differently. Pre‐treating with NaPy, a natural cell metabolite, allows cells under damaging‐level mechanical loads to maintain their PM integrity, that is, to avoid loss of homeostasis and inevitable, eventual cell death, by preventing initial, microscale stages of PU formation. This pre‐treatment may be applied prior to planned periods of immobility, for example, planned surgery or transport, to prolong safe time in a position by preventing initial cell damage that can cascade and lead to PU formation.