Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor long-term outcomes. Numerous studies claim that circular RNAs (circRNAs) are important regulators in AML progression. This study intended to explore the role of circNPM1 in AML development and drug chemoresistance. The expression of circNPM1 and miR-345-5p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cellular activities, including cell growth, apoptosis, cell cycle, migration and invasion, were monitored using colony formation assay, flow cytometry assay and transwell assay, respectively. The relationship between miR-345-5p and circNPM1 or Frizzled-5 (FZD5) was predicted by the bioinformatics tool starBase and validated by dual-luciferase reporter assay or RNA immunoprecipitation (RIP) assay. CircNPM1 was abundantly expressed in serum samples from AML patients and AML cell lines. CircNPM1 silence or miR-345-5p restoration repressed colony formation, cell migration and invasion, contributed to cell apoptosis and cell cycle arrest, and weakened Adriamycin (ADM) resistance of AML cells. MiR-345-5p was a target of circNPM1 and was downregulated in AML serum and cells. MiR-345-5p deficiency reversed the effects of circNPM1 silence. Further, FZD5 was targeted by miR-345-5p, and circNPM1 regulated FZD5 expression by adsorbing miR-345-5p. FZD5 overexpression could block the function of miR-345-5p restoration. CircNPM1 might be a vital regulator for ADM chemoresistance in AML cells, which partly depended on the role of the miR-345-5p/FZD5 axis. Our study presents the view that circNPM1 degradation may be a key strategy in AML resistance therapy.