The matter-antimatter asymmetry underlines the incompleteness of the current understanding of particle physics. Neutrinoless double-beta ($0\nu \beta\beta$) decay may help explain this asymmetry, while unveiling the Majorana nature of the neutrino. The CUORE experiment searches for $0\nu \beta\beta$ decay of $^{130}$Te using a tonne-scale cryogenic calorimeter operated at milli-kelvin temperatures. We report no evidence for $0\nu \beta\beta$ decay and place a lower limit on the half-life of T$_{1/2}$ $>$ 3.8 $\times$ 10$^{25}$ years (90% C.I.) with over 2 tonne$\cdot$year TeO$_2$ exposure. The tools and techniques developed for this result and the 5 year stable operation of nearly 1000 detectors demonstrate the infrastructure for a next-generation experiment capable of searching for $0\nu \beta\beta$ decay across multiple isotopes.