Purpose Radiation therapy (RT) is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced RT technologies enable treatment with large fraction, highly conformal, radiation doses to effect free-radical damage to cellular DNA leading to cell cycle arrest, cell death, and innate immune response stimulation. Experimental Design To understand systemic clinical responses after radiation exposure, high throughput proteomic and metabolomic analyses were performed on plasma obtained from cancer patients at intervals after prostate stereotactic body radiation therapy. Pathway analysis and multivariate analyses were used to delineate molecular alterations following radiation therapy and its correlation with clinical outcomes. Results DNA Damage Response (DDR) and cell cycle signaling increased within the first hour after treatment and returned to baseline by one month. Innate immune response signaling also increased within one hour of treatment but persisted for up to three months thereafter. Furthermore, robust immune responses and metabolite elevations, consistent with an early proinflammatory M1-mediated innate immune activation, were observed in patients in remission, whereas patients experiencing PSA-determined disease progression demonstrated less robust immune responses and M2-mediated metabolite elevations. Conclusion/Discussion To our knowledge, these data are the first report of longitudinal proteomic and metabolomic molecular responses in patients after radiation therapy for cancers. The data supports innate immune activation as a critical clinical response of patients receiving radiation therapy for prostate cancer. Furthermore, we propose that the observed innate immune responses may be generalized to the treatment of other cancer types, potentially informing multidisciplinary therapeutic strategies for cancer treatment.