Although caiman populations are being conserved in some protected areas, they face threats related to human pressure, which may ultimately influence their distribution, abundance, and behavior. In this study, we investigated the population ecology (encounter rate, size structure, sex ratio, and injury frequency) and the effects of human disturbance on Melanosuchus niger and Caiman crocodilus populations in Cantão State Park, southern Brazilian Amazon, Central Brazil. We assessed human pressure on both populations, testing the human disturbance–abundance and human disturbance–size structure relationships. We sampled waterbodies within (lakes) and adjacent to (river) protected areas via nocturnal surveys and captures. Human pressure in the river was assessed and categorized via transects with low, medium, and high levels of disturbance. Our results indicate that C. crocodilus was more abundant than M. niger, with populations of both species mainly composed of juvenile males. We also observed that injuries were more prevalent in juveniles and males. Human disturbance negatively affected C. crocodilus abundance, but no effect was found for M. niger. We found no significant effect of human disturbance on size structure for either species; however, the response for each species differed. Snout–vent length (SVL) decreased with increasing human pressure level in the C. crocodilus population, whereas M. niger showed a greater SVL at higher human pressure levels. Our results suggest that human disturbance related to boat traffic, pollution, riverine population, land use, and human activities negatively influence crocodilian populations in their distribution through a distance–abundance relationship. Additionally, the proximity of settlements and accessibility to protected areas are factors related to human disturbance and should be considered in government decisions and the management of protected areas by environmental agencies. Our results improve our understanding caiman population responses to human disturbance.