Emerging evidence suggests microbial pathogens contribute to digestive cancer risk. Atovaquone - proguanil (A-P), an antimalarial with antiparasitic activity, has been associated with a reduced risk of colorectal cancer (CRC). We conducted a retrospective cohort study using the TriNetX US Collaborative Network, including over 100,000 individuals aged 40-69 years who received A-P, matched 1:1 to controls who received other medications. Incident digestive cancers were analyzed using Cox proportional hazards models. Additionally, we performed a metagenomic analysis of 1,044 fecal samples from 156 individuals to assess the abundance of in CRC-associated microbiota. A-P use was associated with a significant reduction in digestive cancer incidence across all age groups: hazard ratios (HRs) ranged from 0.49 to 0.53 (all  < 0.001). Protective associations extended to pancreatic cancer (HR range, 0.50-0.72). In metagenomic analysis, was the most discriminatory microbial species for CRC ( = 1.8 × 10), detected above threshold in 22.6% of CRC samples versus 1.6% of controls (odds ratio 18.2, 95% CI, 8.2-47.6,  = 2.3 × 10). These findings suggest may be an overlooked microbial risk factor for digestive cancers, and that A-P may offer chemopreventive effects through antiparasitic activity. Prospective studies are needed to evaluate its preventive potential.