Dysregulation of long noncoding RNAs (lncRNAs) has been reported to participate in the process of chemoresistance in multiple cancers, including acute myeloid leukemia (AML). LncRNA zinc finger E-box binding homeobox 2 antisense RNA 1 (ZEB2-AS1) has been reported to be up-regulated in AML. However, the biological role of ZEB2-AS1 remains to be determined. Quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the levels of ZEB2-AS1, miR-142-3p and inositol polyphosphate-4-phosphatase type II B (INPP4B). The cell viability and apoptosis were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Western blotting was applied to analyze levels of BCL2 apoptosis regulator (Bcl-2), BCL2 associated X, apoptosis regulator (Bax), cleaved-caspase-3 and INPP4B. The interaction among ZEB2-AS1, miR-142-3p and INPP4B was verified by dual-luciferase reporter assay and RNA pull-down assay. The levels of ZEB2-AS1 and INPP4B were significantly elevated in AML and chemo-resistance tissues, as well as in THP-1 and THP-1/ADR cells. ZEB2-AS1 elevated the IC50 of ADR, and suppressed cell apoptosis of AML cells, while ZEB2-AS1 increased Bcl-2 expression and decreased the levels of Bax and cleaved-caspase-3. ZEB2-AS1 could enhance the resistance in THP-1 and THP-1/ADR cells. ZEB2-AS1 could sponge miR-142-3p, and ZEB2-AS1 reduced the promotion effect of miR-124-3p on the sensitivity of AML cells. Furthermore, IPNN4B was revealed as a target gene of miR-142-3p. More interestingly, suppression of IPNN4B by shRNA reversed the inhibitory effect of ZEB2-AS1 on the sensitivity of AML cells. LncRNA ZEB2-AS1 promoted ADR resistance of AML via regulating INP4B expression by sponging miR-142-3p, providing a novel therapeutic target for drug resistance of AML.