Domestication is a well-known example of the relaxation of environmentally based cognitive selection that leads to reductions in brain size. However, little is known about how brain size evolves after domestication and whether subsequent directional/artificial selection can compensate for domestication effects. The first animal to be domesticated was the dog, and recent directional breeding generated the extensive phenotypic variation among breeds we observe today. Here we use a novel endocranial dataset based on high-resolution CT scans to estimate brain size in 159 dog breeds and analyze how relative brain size varies across breeds in relation to functional selection, longevity, and litter size. In our analyses, we controlled for potential confounding factors such as common descent, gene flow, body size, and skull shape. We found that dogs have consistently smaller relative brain size than wolves supporting the domestication effect, but breeds that are more distantly related to wolves have relatively larger brains than breeds that are more closely related to wolves. Neither functional category, skull shape, longevity, nor litter size was associated with relative brain size, which implies that selection for performing specific tasks, morphology, and life history does not necessarily influence brain size evolution in domesticated species.