Shifting prey selection has been identified as a mechanism potentially regulating predator–prey interactions, but it may also lead to different outcomes, especially in more complex systems with multiple prey species available. We assessed changing prey selection by lions, the major predator for 12 large herbivore species in South Africa's Kruger National Park. The database was provided by records of found carcasses ascribed to kills by lions assembled over 70 years, coupled with counts of changing prey abundance extending over 30 years. Wildebeest and zebra constituted the most favored prey species during the early portion of the study period, while selection for buffalo rose in the south of the park after a severe drought increased their vulnerability. Rainfall had a negative influence on the proportional representation of buffalo in lion kills, but wildebeest and zebra appeared less susceptible to being killed under conditions of low rainfall. Selection by lions for alternative prey species, including giraffe, kudu, waterbuck, and warthog, was influenced by the changing relative abundance and vulnerability of the three principal prey species. Simultaneous declines in the abundance of rarer antelope species were associated with a sharp increase in selection for these species at a time when all three principal prey species were less available. Hence shifting prey selection by lions affected the dynamics of herbivore populations in different ways: promoting contrasting responses by principal prey species to rainfall variation, while apparently being the main cause of sharp declines by alternative prey species under certain conditions. Accordingly, adaptive responses by predators, to both the changing relative abundance of the principal prey species, and other conditions affecting the relative vulnerability of various species, should be taken into account to understand the interactive dynamics of multispecies predator–prey webs.