Voltage-gated sodium selective ion channel Na(V)1.5 is expressed in the heart and the gastrointestinal tract, which are mechanically active organs. Na(V)1.5 is mechanosensitive at stimuli that gate other mechanosensitive ion channels. Local anesthetic and antiarrhythmic drugs act upon Na(V)1.5 to modulate activity by multiple mechanisms. This study examined whether Na(V)1.5 mechanosensitivity is modulated by local anesthetics. Na(V)1.5 channels were expressed in HEK-293 cells, and mechanosensitivity was tested in cell-attached and excised inside-out configurations. Using a novel protocol with paired voltage ladders and short pressure pulses, negative patch pressure (-30 mmHg) in both configurations produced a hyperpolarizing shift in the half-point of the voltage-dependence of activation (V(1/2a)) and inactivation (V(1/2i)) by about -10 mV. Lidocaine (50 µM) inhibited the pressure-induced shift of V(1/2a) but not V(1/2i). Lidocaine inhibited the tonic increase in pressure-induced peak current in a use-dependence protocol, but it did not otherwise affect use-dependent block. The local anesthetic benzocaine, which does not show use-dependent block, also effectively blocked a pressure-induced shift in V(1/2a). Lidocaine inhibited mechanosensitivity in Na(V)1.5 at the local anesthetic binding site mutated (F1760A). However, a membrane impermeable lidocaine analog QX-314 did not affect mechanosensitivity of F1760A Na(V)1.5 when applied from either side of the membrane. These data suggest that the mechanism of lidocaine inhibition of the pressure-induced shift in the half-point of voltage-dependence of activation is separate from the mechanisms of use-dependent block. Modulation of Na(V)1.5 mechanosensitivity by the membrane permeable local anesthetics may require hydrophobic access and may involve membrane-protein interactions.