Direct road mortality and the barrier effect of roads are typically identified as one of the greatest threats to wildlife. In addition, collisions with large mammals are also a threat to human safety and represent an economic cost to society. We documented and explored the effects of animal-vehicle crashes on human safety in São Paulo State, Brazil. We estimated the costs of these crashes to society, and we summarized the legal perspectives. On average, the Military Highway Police of São Paulo reported 2,611 animal-vehicle crashes per year (3.3% of total crashes), and 18.5% of these resulted in human injuries or fatalities. The total annual cost to society was estimated at R$ 56,550,642 (US $ 25,144,794). The average cost for an animal-vehicle crash, regardless of whether human injuries and fatalities occurred, was R$ 21,656 (US $ 9,629). The Brazilian legal system overwhelmingly (91.7% of the cases) holds the road administrator liable for animal-vehicle collisions, both with wild and domestic species. On average, road administrators spent R$ 2,463,380 (US $ 1,005,051) per year compensating victims. The logical conclusion is that the Brazilian legal system expects road administrators to keep animals, both wild and domestic species, off the road. We suggest an improved coordination between the laws that relate to animal-vehicle collisions and human safety, and the process for environmental licenses that focusses on reducing collisions with wildlife and providing habitat connectivity. In addition, we suggest better management practices, raising awareness and social change with regard to abandoned domesticated animals including horses, cattle, and dogs. This should ultimately result in a road system with improved human safety, reduced unnatural mortality for both domestic and wild animal species, safe crossing opportunities for wildlife, and reduced monetary costs to society.