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Abstract There are great concerns for sensing using flexible acoustic wave sensors and lab-on-a-chip, as mechanical strains will dramatically change the sensing signals (e.g., frequency) when they are bent during measurements. These strain-induced signal changes cannot be easily separated from those of real sensing signals (e.g., humidity, ultraviolet, or gas/biological molecules). Herein, we proposed a new strategy to minimize/eliminate the effects of mechanical bending strains by optimizing off-axis angles between the direction of bending deformation and propagation of acoustic waves on curved surfaces of layered piezoelectric film/flexible glass structure. This strategy has theoretically been proved by optimization of bending designs of off-axis angles and acoustically elastic effect. Proof-of-concept for humidity and ultraviolet-light sensing using flexible SAW devices with negligible interferences are achieved within a wide range of bending strains. This work provides the best solution for achieving high-performance flexible acoustic wave sensors under deformed/bending conditions.