Rabies is a lethal viral zoonosis that requires intensive surveillance and prophylaxis efforts in several countries. Our objective was to describe the epidemiological profile of human anti-rabies consultations recorded in the database of a public regional health division of the most populous state in Brazil between 2014 and 2023, to evaluate the prophylactic measures instituted, and to estimate the direct costs associated with different post-exposure treatment regimens. This is a retrospective, descriptive study based on 54,977 notifications of human anti-rabies consultations from a region comprising approximately 68 municipalities in the State of São Paulo, analyzed using descriptive statistics. The measures were classified as adequate, insufficient, or excessive, according to the guidelines of the Brazilian Ministry of Health. Costs were estimated based on the number of treatments and the average values of the immunobiologicals administered. More than half of the prophylaxis procedures were carried out in situations considered to be low-risk. Children between 1 and 19 years of age comprise the age group with the highest number of consultations. Approximately 42.4% of the measures instituted were classified as inadequate, with a predominance of excessive measures in low-risk situations, such as indirect contact and aggressions by healthy animals. Dogs (80.1%) and cats (14.1%) cited as aggressors accounted for nearly all recorded consultations. The measures in severe exposures and those involving wild animals showed greater adherence to the guidelines of the official protocol. Treatment was discontinued in 20.6% of cases, mainly due to abandonment. The total estimated cost was approximately BRL 15.5 million, of which about 20% corresponded to inadequate measures, representing potentially avoidable expenditures. The adoption of measures more aligned with the guidelines may improve clinical effectiveness and the efficiency of public resource use.