Indium sesquioxide is the most widely used conductive oxide for optoelectronic applications. The isolation of a novel orthorhombic phase of In2O3 at ambient pressures opens a new avenue for tuning the materials properties. Through an explicit comparison of the stable bixbyite and metastable orthorhombic phases of In2O3, using a hybrid density functional theory approach, we assess the impact of the loss of inversion symmetry and the distortion of the oxide sublattice on the electronic and defect structure. The band structure of the orthorhombic phase retains the key features of a transparent conductive oxide, with a large separation between the fundamental and optical band gaps. The dominant point defect—the oxygen vacancy—shows similar behavior in both phases with the coexistence of a localized defect wave function in the neutral state and a resonant transition level to the positively charged state. The natural valence band alignment between the cubic and orthorhombic phases is estimated to be 0.22 eV.