Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin’s lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the (nucleophosmin 1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently FDA approved for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of pro-apoptotic protein BAD, and decreased expression of anti-apoptotic proteins survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell cycle analysis indicates gilteritinib induced G0/G1 cell cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK-fusion driven hematologic or solid malignancies. Implications: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK driven anaplastic large cell lymphoma cells and pave a path for developing future clinical trials.