Controlling the electromechanical response of piezoelectric biological structures including tissues, peptides, and amino acids provides new applications for biocompatible, sustainable materials in electronics and medicine. Here, the piezoelectric effect is revealed in another class of biological materials, with robust longitudinal and shear piezoelectricity measured in single crystals of the transmembrane protein ba3 cytochrome c oxidase from Thermus thermophilus. The experimental findings from piezoresponse force microscopy are substantiated using a range of control measurements and molecular models. The observed longitudinal and shear piezoelectric responses of ≈2 and 8 pm V−1, respectively, are comparable to or exceed the performance of commonly used inorganic piezoelectric materials including quartz, aluminum nitride, and zinc oxide. This suggests that transmembrane proteins may provide, in addition to physiological energy transduction, technologically useful piezoelectric material derived entirely from nature. Membrane proteins could extend the range of rationally designed biopiezoelectric materials far beyond the minimalistic peptide motifs currently used in miniaturized energy harvesters, and the finding of robust piezoelectric response in a transmembrane protein also raises fundamental questions regarding the molecular evolution, activation, and role of regulatory proteins in the cellular nanomachinery, indicating that piezoelectricity might be important for fundamental physiological processes. Piezoelectricity, the functional solid‐state property that converts force into voltage and vice versa, is demonstrated in a transmembrane protein, completing a “missing link” in the hierarchy of biological materials. The magnitudes of the piezoelectric coefficients are revealed through comprehensively benchmarked experiments and extensive molecular modeling. The results confirm transmembrane proteins as a promising source of sustainable, eco‐friendly, high‐performance, piezoelectric materials.