Abstract: The P2Y14 receptor (P2Y₁₄R) contributes to inflammatory responses in sepsis, but pharmacological opportunities for targeting this receptor remain limited. We screened a natural product library using a structure-based approach and tested four selected compounds for P2Y₁₄R antagonism. Caftaric acid was the most active candidate (IC₅₀ = 5.631 μmol·L⁻¹). Cellular thermal shift assays indicated target engagement, and surface plasmon resonance measured direct binding (KD = 10.11 μmol·L⁻¹). Mutation of Lys176 to alanine abolished the functional antagonism by caftaric acid. In mice with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis, caftaric acid pretreatment improved survival and reduced systemic inflammation and organ injury. Myeloid-specific P2ry14 deletion produced a similar protective phenotype, with no significant additional benefit from caftaric acid. In LPS/IFN-γ-stimulated macrophages, caftaric acid reduced inflammatory mediators and STAT1-associated signaling, improved mitochondrial membrane potential, and increased the mt-Keima-defined mitophagy-high population. Silencing P2ry14 or Stat1 likewise reduced inflammation and increased mitophagy-high cells, whereas subsequent caftaric acid treatment produced no significant further change. Together, these data support P2Y₁₄R antagonism by caftaric acid and implicate P2Y₁₄R–STAT1 signaling and macrophage mitophagy in its protective effects under pretreatment conditions.