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Colorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53−/− colorectal cancer cells treated with these drugs and report pan-drug, drug-specific, drug class-specific, p53-independent, and p53-dependent signatures. We observed downregulation of histone genes by 5-FU (that significantly correlates with improved survival in CRC patients) and upregulation of FOS and ATF3 by oxaliplatin (which may contribute to peripheral neuropathy). BTG2 was identified as a top gene upregulated by all four drugs, suggesting its critical role in the cellular response to chemotherapy in CRC. Soluble TRAILR2 (death receptor 5; DR5) is a decoy receptor for TRAIL, an apoptosis-inducing cytokine. TRAILR2 was down-regulated by oxaliplatin and 5-FU, was not affected by CPT-11, and was increased by cisplatin. There was an increase in IL-8 by oxaliplatin and increase in ferritin by cisplatin which may contribute to cancer cell survival. Novel drug-specific mechanisms of efficacy or toxicity identified in these signatures may be targeted with combination therapies or development of new targeted therapies. Together, the findings here contribute to our understanding of the molecular bases of efficacy and toxicity of chemotherapeutic agents often used for treatment of GI cancer such as CRC.