Biodiversity conservation in developing countries is faced with many and mounting challenges, including increasing human–wildlife conflicts (HWCs). In Africa and other developing countries, increasing HWCs, particularly those adjacent to protected areas, can adversely affect local stakeholder perceptions and support for conservation. We analyzed HWC reports for multiple wildlife species compiled >23 years (1995–2017) from the Greater Tsavo Ecosystem (GTE) in Kenya to determine HWC trends. The GTE is the largest protected area in Kenya, covering 22,681 km2. Overall, 39,022 HWC incidents were reported in 6 GTE regions (i.e., Taveta, Mutomo, Kibwezi, Rombo, Galana, Bachuma). The 5 wildlife species most often implicated in HWC incidents were the African elephant (Loxodonta africana, 61.6%, n = 24,032), nonhuman primates (11.5%, n = 4,480), buffalo (Syncerus caffer, 6.2%, n = 2,432 ), African lion (Panthera leo, 4.2%, n = 1,645), and the hippopotamus (Hippopotamus amphibius, 3.8%, n = 1,497). The HWC reports also revealed spatial distinctions across the 6 GTE regions. More human–elephant conflicts (HECs; 43.3%, n = 10,427) were reported in the Taveta region than other regions. The Mutomo region was the epicenter of primate, snake, and python (Python spp.) conflicts. More large carnivore depredations on livestock were reported in the Taveta, Rombo, and Mutomo regions. Lions, spotted hyenas (Crocuta crocuta), and leopards (P. pardus) were implicated in more livestock depredations than other carnivores. The number of HWCs reported varied by year and season and were related to similar variations in the availability, quality, and distribution of food and water governed by rainfall fluctuations. Reported HECs were positively and linearly related to human, elephant, and livestock population densities. The Kenya Wildlife Service responded to >90% of the reported HWCs. In general, the number of HWCs and trends reported were higher in the regions that also exhibited the highest human population growth rates and densities. Sustainable biodiversity conservation in human-dominated landscapes is contingent upon communities deriving meaningful benefits from wildlife conservation. Far-sighted measures and different conservation approaches are required to mitigate HWCs in communities neighboring protected areas.