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Several bacterial taxa enriched in inflammatory bowel diseases and colorectal cancer (CRC) are found in the oral cavity. We conducted a pilot study nested within a six-week aspirin intervention in a randomized placebo-controlled trial to test their response to aspirin intervention. Fifty healthy subjects, 50–75 years old, were randomized to receive 325 mg aspirin (n = 30) or placebo (n = 20) orally once daily for six weeks. Oral tongue swabs were collected at baseline and week six. We estimated the association between aspirin use and the temporal changes in the relative abundance of pre-specified genus level taxa from pre- to post-treatment. The temporal change in relative abundance differed for eight genus level taxa between the aspirin and placebo groups. In the aspirin group, there were significant increases in the relative abundances of <i>Neisseria</i>, <i>Streptococcus</i>, <i>Actinomyces</i>, and <i>Rothia</i> and significant decreases in <i>Prevotella</i>, <i>Veillonella</i>, <i>Fusobacterium</i>, and <i>Porphyromonas</i> relative to placebo. The log ratio of <i>Neisseria</i> to <i>Fusobacterium</i> declined more in the aspirin group than placebo, signaling a potential marker associated with aspirin intervention. These preliminary findings should be validated using metagenomic sequencing and may guide future studies on the role of aspirin on taxa in various oral ecological niches.