Colorado potato beetle is a serious defoliator of potatoes that has a long record of developing insecticide resistance. Therefore, new active ingredients are important for continuous successful control of this pest. RNAi is a potentially powerful technology allowing to design such insecticides. We conducted a series of experiments testing the effects of ledprona (CalanthaTM). This is a novel RNAi-based insecticide that targets synthesis of the proteasome subunit beta 5, thus impeding the removal of damaged proteins in the cells. Beetles exposed to ledprona suffered increased mortality and decreased foliage consumption in all four instars and adult beetles, although the effects became more pronounced from earlier to later life stages. No ovicidal activity was detected. Onset of mortality was slower compared to the existing chemical insecticides. Beetles surviving sublethal concentrations of ledprona had lower pupation success, fecundity, and mobility. In field trials, beetle control was comparable to that provided by spinosad and chlorantraniliprole. Overall, CalanthaTM shows a good potential for protecting potato crops from Colorado potato beetle damage and is likely to be a good fit in integrated pest management programs.