Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent type of post-transcriptional RNA modification mediated by adenosine deaminase acting on RNA enzymes (ADARs). Inosine is interpreted as guanosine by the cellular machinery, thus impacting RNA activity and protein recoding. Here, with a comprehensive analysis of over 98,000 RNA editing sites across six cancer types in The Cancer Genome Atlas (TCGA) database, where tumor samples were stratified as sensitive or resistant to 18 anti-cancer drugs, we systematically identified 7,157 differential editing sites (DESs), indicating their potential response to treatment. The DESs were validated in cancer cell lines from Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC). Validation through a completely independent dataset revealed that RNA editing might be an important determinant of mediating anti-cancer drug response with higher confidence. These DESs were preferentially located in 3’-untranslated regions (3’UTRs), consistently in both tumor tissues and cancer cell lines, potentially impacting microRNA-mediated gene regulation and contributing to drug resistance. Additionally, most of the prognosis-linked DESs have consistent editing patterns in the patients with poor overall survival and therapy resistance, but not in the drug-sensitive samples. We also discovered that some drug resistance-related RNA-binding proteins might mediate editing levels of the DESs by competing for substrates with ADARs. Collectively, we characterized the pharmacogenomic landscape of A-to-I RNA editing in cancers and dissected the potential regulatory mechanism of drug resistance from the perspective of RNA editing, which might provide new therapeutic targets for overcoming drug resistance.