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QCD instantons are arguably the best motivated yet unobserved nonperturbative effects predicted by the Standard Model. A discovery and detailed study of instanton-generated processes at colliders would provide a new window into the phenomenological exploration of QCD and a vastly improved fundamental understanding of its non-perturbative dynamics. Building on the optical theorem, we numerically calculate the total instanton cross-section from the elastic scattering amplitude, also including quantum effects arising from resummed perturbative exchanges between hard gluons in the initial state, thereby improving in accuracy on previous results. Although QCD instanton processes are predicted to be produced with a large scattering cross-section at small centre-of-mass partonic energies, discovering them at hadron colliders is a challenging task that requires dedicated search strategies. We evaluate the sensitivity of high-luminosity LHC runs, as well as low-luminosity LHC and Tevatron runs. We find that LHC low-luminosity runs in particular, which do not suffer from large pileup and trigger thresholds, show a very good sensitivity for discovering QCD instanton-generated processes.