Platelets, anucleate cells derived from megakaryocytes, are increasingly recognized as active participants in immune surveillance. Although platelet RNA primarily originates from megakaryocytes, platelets also internalize and sequester extracellular nucleic acids, including cell-free DNA (cfDNA). Excess cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA from plasma and that clinically relevant insights may be derived from the analysis of DNA fragments contained within platelets. Using live imaging, flow cytometry, and sequencing approaches, we detected DNA within ∼8% of healthy donor platelets, including older, RNA-depleted platelets. In maternal samples, Y-chromosome fragments were detected, confirming that platelet DNA is not solely derived from parent megakaryocytes but also sequestered during circulation. Whole-genome and methylation sequencing revealed that platelet DNA closely resembles cfDNA, predominantly originating from leukocytes and megakaryocytes. In a low-platelet model, depletion led to increased plasma DNA, supporting a role for platelets in DNA clearance. Platelets also internalized tumor-derived DNA from cocultured cancer cells, with mutations remaining detectable despite DNase treatment, suggesting that platelets sequester DNA and protect it from degradation. Furthermore, pharmacologic manipulation confirmed that DNA uptake is an active process influenced by platelet activation. Importantly, platelet sequencing detected tumor-specific mutations in cancer and premalignant patients, supporting their role as a novel liquid biopsy source. Overall, these findings redefined platelets as circulatory “sentinels” of genomic perturbations and highlighted the potential of platelet-derived DNA analysis in disease monitoring and early cancer detection.