The production of native oysters Crassostrea rhizophorae and Crassostrea gasar is expanding in northeastern Brazil, where reports of bivalve pathology are scarce. Recently, Perkinsus marinus was detected for the first time infecting C. rhizophorae in the state of Paraíba, in northeastern Brazil. Thus, more information on factors affecting the health of oysters is needed, especially concerning the pathogens listed by the World Organisation for Animal Health (OIE). The current study evaluated the health status of wild and cultured C. gasar mangrove oysters from the estuary of the Rio São Francisco, Sergipe state, northeastern Brazil. Results show that C. gasar oysters cultivated in the Rio São Francisco estuary had a greater prevalence of diseases and pathogens than oysters from a natural population in the same estuary, including maladie du pied (shell disease), Rickettsia—like organisms in gills, Steinhausia sp. oocyte infections, and Polydora sp. valve infestations. Of the two OIE notifiable diseases investigated, perkinsosis occurred at variable levels of prevalence that were always greater among cultured oysters (50.8%) than wild oysters (25.8%), and the intensity was predominantly low, suggesting low mortality impact. Bonamiosis was not detected.