Recent studies found circRNAs were involved in tumorigenesis and became new tumor biomarkers and therapeutic targets in lung adenocarcinoma (LUAD), which played a critical role in various biological processes and had been implicated in resistance to chemotherapeutic drugs. However, the role of CDR1-AS in chemoresistance of LUAD to pemetrexed (PTX) and cisplatin (CDDP) is poorly understood. Here, we found that CDR1-AS was up-regulated in LUAD tissues and cell lines, its high-expression was relevant to smoking history, T stage and neoadjuvant chemotherapy (PTX and CDDP) of LUAD patients. CDR1-AS was an independent prognostic biomarker for LUAD patients. CDR1-AS was highly expressed in PTX and CDDP resistant LUAD tissues and cell line (A549/CR). Silence of CDR1-AS re-sensitized A549/CR cells to PTX and CDDP. CDR1-AS was closely related with EGFR/PI3K signaling pathway in A549/CR cells. The activating of EGFR/PI3K pathway mostly restored the effecting of CDR1-AS silence on PTX and CDDP sensitivity in A549/CR cells, CDR1-AS contributed to PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD. In conclusion, the CDR1-AS is high-expressed in LUAD and is an independent prognostic biomarker for LUAD patients. The high-expression of CDR1-AS is related with the PTX and CDDP insensitivity of LUAD patients, CDR1-AS promotes PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD.