The refinement of high-performing scintillator compounds is critical to the advancement of time-of-flight positron emission tomography (TOF-PET). Here, we characterize 2nd, 4th, and 5th generation cerium-doped, calcium co-doped lutetium–yttrium oxyorthosilicate (LYSO) crystals developed and supplied by Luxium Solutions in terms of light yield, emission spectra, non-proportionality, and decay time. Additionally, the samples are coupled to a Philips 3200 digital photon counter (DPC) for a comparison of performance as a detector component. The detector sensitivity, energy resolution, and coincidence resolving time (CRT) of the crystals are measured at −25 °C. The 4th and 5th generation crystals are shown to have similar light yields and decay times at room temperature, and outperform the 2nd generation crystals in all measured characteristics. The detectors making use of 5th generation crystals had markedly better sensitivity, energy resolution, and CRT values than their 4th generation counterparts.