Ultra-high temperature transition-metal ceramics are potential candidates for fusion reactor structural/plasma-facing components. We reveal the irradiation damage microstructural phenomena in Boron-11 enriched titanium diboride (TiB2) using mixed-spectrum neutron irradiations, combined with state-of-art characterization using transmission electron microscopy (TEM) and high resolution TEM (HRTEM). Irradiations were performed using High Flux Isotope Reactor at ∼220 and 620 °C up to 2.4 x 1025 n.m−2 (E > 0.1 MeV). Total dose including contribution from residual Boron-10 (10B) transmutation recoils, was ∼4.2 displacements per atom. TiB2 is susceptible to irradiation damage in terms of dislocation loop formation, cavities and anisotropic lattice parameter swelling induced micro-cracking. At both 220 and 620 °C, TEM revealed dislocation loops on basal and prism planes, with nearly two orders of magnitude higher number density of prism-plane loops. HRTEM, electron diffraction and relrod imaging revealed additional defects on {101̅0} prism planes, identified as faulted dislocation loops. High defect cluster density on prism planes explains anisotropic a-lattice parameter swelling of TiB2 reported in literature which caused grain boundary micro-cracking, the extent of which decreased with increasing irradiation temperature. Dominance of irradiation-induced defect clusters on prism planes in TiB2 is different than typical hexagonal ceramics where dislocation loops predominantly form on basal planes causing c-lattice parameter swelling, thereby revealing a potential role of c/a ratio on defect formation/aggregation. Helium generation and temperature rise from residual 10B transmutation caused matrix and grain boundary cavities for the irradiation at 620 °C. The study additionally signifies isotopic enrichment as a viable approach to produce transition-metal diborides for potential nuclear structural applications.