Fisheries interactions with non-target marine vertebrates are a worldwide problem. The impact of coastal bottom trawl fisheries on marine mammals has never been evaluated before in the Río de la Plata Estuary and the adjacent Atlantic Ocean. Our aim was estimating the bycatch per unit effort (BcPUE) and incidental mortality rates of marine mammals caused by the industrial coastal bottom trawl fisheries fleet. We evaluated the mortality of three species (i.e., franciscana dolphin Pontoporia blainvillei, South American sea lion Otaria flavescens, and the South American fur seal Arctocephalus australis); these species are facing conservation problems either at the regional or local scale. We conducted an onboard data collection program of marine mammals’ bycatch involving crew members of 10 vessels (30%) of the Uruguayan coastal bottom trawl fleet between January 2009 and April 2012. A total of 102 marine mammal individuals were bycaught during 490 fishing trips involving 2,398 fishing days. Mortalities estimated for franciscana dolphin were the highest among the species affected, with values adding up to ~100 individuals for year (with scenarios of population decline in the area), followed by South American sea lion with ~77 individuals by year (0.8% of local population) and the South American fur seal with an annual mortality estimate of ~25 individuals (~0.02% of local population). BcPUE showed significant temporal variation, with franciscana dolphin BcPUE varying seasonally and those of otariids according to their breeding season. Our estimates of marine mammal bycatch by bottom trawl fisheries should constitute an important input for the sustainable management of fisheries and the conservation of marine biodiversity in the southwestern Atlantic Ocean.