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Globally, the bycatch of marine mammals in fisheries represents the greatest source of human-caused mortality that threatens the sustainability of many populations and species. The Australian sea lion (Neophoca cinerea) is an endangered species, whose populations off South Australia (SA) have been subject to bycatch in a demersal gillnet fishery targeting sharks since the 1960s. A comprehensive assessment was undertaken of sea lion bycatch mortality that combined independent fishery observer data with species distribution models (underpinned by satellite tracking, abundance data and population modeling) to model the relationship between at-sea foraging effort and bycatch rate. Combined with the distribution of fishing effort, these models enabled the overall level of bycatch mortality to be estimated by age, sex and subpopulation, facilitating population viability analyses that indicated most subpopulations were declining, and subject to unsustainable levels of bycatch mortality. To reduce this mortality, the Australian Fisheries Management Authority implemented an Australian Sea Lion Management Strategy that included an independent observer program (ultimately 100% electronic monitoring of gillnet fishing off SA), permanent spatial gillnet closures around all sea lion breeding sites, bycatch mortality limits that triggered temporal (18 months) spatial closures when zone-specific bycatch trigger limits were reached, and incentives for gillnet fishers to switch to an alternate fishing method (longlines). The Strategy had immediate impacts on the fishery: it resulted in significant reductions in gillnet fishing effort and on the reported bycatch of sea lions. In the next decade, there was an estimated 98% reduction in sea lion bycatch mortality from gillnet interactions and an apparent stabilization of the decline in sea lion pup abundances at some impacted breeding sites. There was an almost complete transition in the fishery from gillnets to longlines, and fishing catches returned to pre-management levels. The successful implementation of management measures to mitigate sea lion bycatch mortality in the gillnet fishery off SA was rapid, science informed, adaptive, comprehensive, and backed by strong compliance and monitoring of the fishery. It provides an important case study which demonstrates how management measures can be effectively applied to mitigate bycatch mortality of marine mammals and other marine protected species.