Cu2Sb-type (Strukturbericht designation: C38) intermetallic compound Mn2Sb was studied up to 25.7 GPa at room temperature using the in situ synchrotron powder X-ray diffraction (XRD) technique. Our results from the XRD analysis showed that the (C38)-type Mn2Sb undergoes a pressure-induced structural phase transition near 22.4 GPa. In the low-pressure (LP) phase of Mn2Sb, an anisotropic compressibility was observed with greater compressibility along the a-axis than the c-axis. And the mechanism for the anisotropy of compressibility was discussed in terms of the stacking of crystallography. Fitted to a third-order Birch–Murnaghan equation of state (BM-EOS), the pressure–volume data of Mn2Sb yielded the stable lattice volume V0 = 109.45(3) Å3, bulk modulus B0 = 50.1(5) GPa, and its derivative = 7.0(2) for the LP phase. We propose that the distortion of Mn(I)Sb4 tetrahedra may give rise to the structural instability of Mn2Sb under high pressure (HP).