The deformability of cancer cells is associated with cell invasive behavior and may thus play a critical role in metastasis. An oversimplified view in the literature is that cancer cells become more deformable as they become more invasive. β-adrenergic receptor (βAR) signaling drives invasion and metastasis, but the effects on cell deformability are not known. Here we show that activation of β-adrenergic signaling by βAR agonists reduces the deformability of highly metastatic human breast cancer cells, and that these stiffer cells are more invasive in vitro.  We find that βAR activation also reduces the deformability of ovarian, prostate, melanoma, and leukemia cells. Mechanistically, we show that βAR-mediated cell stiffening depends on the actin cytoskeleton and myosin II activity. These changes in cell deformability can be prevented by pharmacologic β-blockade or genetic knockout of the β₂-adrenergic receptor. Our results identify a β₂-adrenergic-Ca²⁺-actin axis as a novel regulator of cell deformability, and suggest that the relationship between cell mechanical properties and invasion may be dependent on context. The findings suggest that the use of cell mechanotype as a biomarker may not be appropriate for patients with elevated βAR signaling, such as those who are stressed at diagnosis. Ongoing studies are defining how β₂AR regulation of deformability may enable cancer cells to obtain a selective advantage for invasion and growth in secondary organs, and probing the role of cell physical and mechanical properties in the anti-cancer effects of pharmaceutical strategies that target βAR such as β-blockers.