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Galactic cosmic radiation (GCR) exposure is increased to space flight crews as travel moves beyond low Earth orbit. GCR includes high energy protons and heavy ionizing ions such as 56Fe, 28Si, and 16O and there are distinct differences in the biological response compared to low‐energy transfer events (x‐rays). Although the exposure rate is relatively low, the cumulative radiation dose is likely to have deleterious effects for long duration flight crews. The underlying mechanisms for these elevated risks are thought to include direct DNA damage as well as chronically elevated oxidant stress, and inflammation. Given the relatively low fluence rate of GCR exposure during flight operations it might be possible to manage these deleterious effects using small molecules currently available. To that end we have utilized a FDA approved drug library to perform a high throughput screen of cultured cells following exposure to GCR. H9c2 cells were exposed to a single 75 cGy dose using the 5‐ion GCRsim protocol developed by NSRL. Following GCRsim exposure, cells were treated using 10 µM for each drug. At harvest, cells were tested for protein content, oxidant stress, cellular senescence, and mitochondrial function. Of 725 drugs, more than 500 were ineffective in managing GCR exposure. Within the top 160 drugs, 33 were primarily designated as anti‐inflammatory. Significant variations within drug classes were observed. Only 10 of 46 drugs that interacted with histamine receptors were found useful and most were 5‐HT3 specific. The COX inhibitors deemed useful were all COX2 specific. Surprisingly, some anti‐diabetic medications observed to be useful including metformin. The bias of mitochondrial degradation as a central readout comes from several “omics” analyses that identified mitochondrial dysfunction as a consequence of GCR exposure. Mitochondrial dysfunction is also an antecedent event in the transformation leading to carcinogenesis. And the potential for carcinogenesis is a significant risk for long duration space missions. Separate from examining mitochondrial and cellular dysfunction as readouts, we have developed a Afp‐tdTomato expressing cell line that is responsive to different carcinogenic reagents including GCR. We have observed that some of the lead candidates will at least partially rescue the cells from GCR induced Afp driven expression. Additionally adapting cell doubling time protocols we observed that GCR exposure significantly increased cell doubling time; a finding indicative of mitotic dysfunction. We also observed that this increase was partially ameliorated by some of the lead candidates. That no one class of drug dominated the response to radiation exposure speaks to the complexity of managing GCR exposure.