The orthorhombic polymorph of Ca₂Zr₅Ti₂O₁₆ (space group Pbca) has been studied by powder X-ray diffraction under high pressures up to 30 GPa using synchrotron radiation. We have found evidence of a structural phase transition at 12−13 GPa. The phase transition causes an enhancement of the crystal symmetry. The high-pressure phase is tetragonal, being described by space group I4₁/acd. The space groups of the high- and low- pressure phases have a group/subgroup relationship. However, the phase transition is accompanied by a discontinuous change in the unit-cell volume, indicating that the phase transition can be classified as first order. We have also performed density functional theory calculations. These simulations support the occurrence of the orthorhombic-to-tetragonal transition. The pressure−volume equation of state and axial compressibilities have been determined for both polymorphs. The results are compared with previous studies in related oxides.