The catfish Calophysus macropterus is heavily exploited in the Amazon basin, yet its life history characteristics are poorly documented, hampering proper fisheries management. In order to fill this gap, monthly sampling in the upper Putumayo River and in the Amazonas, lower Marañón and Ucayali (AMU) rivers were carried out over several years (2013–2015 in the AMU, 2013–2017 in the Putumayo) to provide detailed information about its reproduction, growth and mortality patterns (using length frequency data). Reproduction, which occurs during the dry and early flooding season, was only observed in the upper Putumayo River and not in the sampled portion of the AMU system, suggesting that the species reproduces closer to the Andes than other pimelodid catfishes. Size at first sexual maturity did not differ significantly among sex or among river systems, ranging from 25–28 cm SL. In both river systems, females had a faster growth than males and both genders also tended to have a better growth in the AMU than in the upper Putumayo. Mortality and exploitation estimate all indicated overexploitation of the species in both river systems. The implications of these results for fisheries management and conservation are discussed.