Sorption-based Joule–Thomson coolers operate vibration-free, have a potentially long life time, and cause no electromagnetic interference. Therefore, they are appealing to a wide variety of applications, such as cooling of low-noise amplifiers, superconducting electronics, and optical detectors. The required cooling temperature depends on the device to be cooled and extends into the cryogenic range well below 80 K. This paper presents a generalized methodology for optimization in a sorption-based JT cooler. The analysis is based on the inherent properties of the fluids and the adsorbent. By using this method, the working fluid of a JT cooler driven by a single-stage sorption compressor is optimized for two ranges of cold-tip operating temperatures: 65–160 K and 16–38 K. The optimization method is also extended to two-stage compression and specifically nitrogen and carbon monoxide are considered.