The light emission performance of the X-ray excited CsI:Tl single-crystal scintillator was investigated as a function of X-ray tube voltage and crystal thickness. Four CsI:Tl single-crystal layers (CRYOS Ltd., Ukraine) with thickness from 1 to 7 mm were irradiated employing two X-ray tube voltage ranges: (i) the 22–45 kV (molybdenum anode–molybdenum filter (Mo/Mo)) range, employed in mammographic imaging and (ii) the 40–140 kV (tungsten anode–aluminum filter) tube voltage range, used in general X-ray projection and tomographic imaging. The X-ray luminescence efficiency (light emission spectrum over incident X-ray fluence) of the crystals was determined by performing light emission spectrum and X-ray exposure measurements. In addition, the intrinsic conversion efficiency (fraction of the absorbed X-ray converted into light) and the spectral compatibility to various optical detectors were estimated from these measurements. The luminescence efficiency was found to be a nonlinear function of crystal thickness and of X-ray tube voltage. Peak efficiency (29.5 μWm−2/mRs) was observed for the 5 mm thick crystal at 140 kV. A secondary efficiency peak was observed at 42 kV (Mo anode) probably due to the effect of the K-photoelectric absorption edge (at 33 and 35 keV for Cs and I, respectively). For the thicker (7 mm) crystal, the efficiency was found to decrease due to light attenuation effects within the scintillator mass.