ABSTRACT Host microbiomes play a key role in coral disease dynamics; thus, it is essential to characterize microbial communities of diseased tissues and identify how they are altered by potential treatments, especially as coral reef populations continue to decline globally. The abundance of Orbicella faveolata, a major reef-building Caribbean coral species, has significantly declined due to several stressors, including infectious disease. Caribbean yellow band disease (CYBD) often results in complete colony mortality. We applied an amoxicillin-laced Base2B ointment to CYBD lesion areas on O. faveolata within Buck Island Reef National Monument, St. Croix, USVI, trying to halt disease progression. Another CYBD lesion area on the same colony served as a paired untreated control. Microbiomes of the apparently healthy tissue adjacent to the treatment were characterized pretreatment and 2 days post-treatment, along with the paired untreated CYBD controls and nearby healthy colonies. Both microbiomes of untreated CYBD lesions and apparently healthy tissue on CYBD colonies had a significantly higher alpha diversity and significantly differed from those of nearby healthy colonies, suggesting potential systemic effects of CYBD. Amoxicillin treatment significantly changed the microbial community composition of tissues adjacent to the treatment site. The relative abundance of the bacterial family Vibrionaceae , a putative pathogen for CYBD and often associated with other coral diseases, was enriched post-treatment. However, the lesion progression rates of treated and untreated lesion areas were similar. Our results suggest that amoxicillin may disrupt the microbiome of adjacent tissue on O. faveolata , allowing for opportunistic Vibrio sp. bacteria to colonize, and may not be an effective treatment for CYBD. IMPORTANCE Orbicella faveolata , a primary reef-building coral species in the Caribbean, has been severely impacted by Caribbean yellow band disease. This disease causes tissue loss, which often culminates in the complete loss of the colony since recovery is rarely observed. The present study is significant because the development of an effective long-term treatment for Caribbean yellow band disease and understanding how the microbial partners contribute to pathogenesis are essential for conserving Caribbean coral reefs. While treatment with amoxicillin was not effective, our study uncovered valuable insights into the microbial composition of Caribbean yellow band disease in O. faveolata . In addition, this study highlights the possible unintended negative effects of treatment with amoxicillin and casts doubt on Vibrionaceae as the culprit of this disease.