Abstract Extreme wildfire events, such as the Pantanal 2020 megafires, are expected to become more common. Assessing the impacts of such extreme events on wildlife is imperative for conservation planning. Direct observation of carcasses can provide valuable information on how these impacts relate to spatial heterogeneity. Here, we use double‐observer carcass surveys to assess the numbers and spatial patterns of direct mortalities of medium‐ to large‐sized mammals resulting from the Pantanal 2020 megafires in a large reserve (1080 km2) in the northern Pantanal wetland. Accounting for imperfect detection, we model the spatial variation in mortality occurrence and abundance, testing the effects of habitat‐related variables and wildfire severity using multi‐species N‐mixture models. We found that 26 out of 27 species of medium and large‐sized mammals died from the fires with a mean estimate of around 49 thousand individuals. The most affected species included capuchin monkeys, agoutis, peccaries, tapirs, brocket deer, tamanduas, coatis and capybaras. Direct mortality of mammals by wildfires was affected by landscape factors related to species habitats, species traits (probably related to escape or refuge strategies), and the intensity of the wildfires. Mortalities presented a general positive relationship with non‐flooded forests (a fire‐sensitive habitat in Pantanal) and with the severity of wildfires. Artificial water bodies, a common landscape structure in Pantanal, had 7.5 times more deaths than other areas. Synthesis and applications: With the approach used, we were able to: (i) identify mortality hotspots associated with landscape features; (ii) simultaneously identify the most affected species and assess the average relationships for all the assemblage of medium‐ and large‐sized mammals. We discuss conservation and management actions in two contexts: species prioritization for rescuing and monitoring; and territory prioritization for fire prevention and fighting.