The therapeutic effects of off-label oral vancomycin in pediatric and adult primary sclerosing cholangitis (PSC)-inflammatory bowel disease, more commonly PSC-ulcerative colitis (UC), indicate the translational relevance of disease-associated microbiome findings. This is the first report on longitudinal salivary and fecal microbiome changes in a pediatric PSC-UC patient over the first 90 days of vancomycin therapy. Increase in bacterial diversity and abundance changes in Fusobacterium, Haemophilus, and Neisseria were observed. Our findings highlight the importance of longitudinal microbiome sampling in PSC-UC and serve as a nidus for larger-scale observations toward advancing microbial therapeutics for PSC.