Lung cancer is the leading cause of global cancer-associated mortality, therefore it is important to reveal the molecular mechanisms of lung cancer progression and to develop novel therapeutic targets. The results of the present study identified that manganese-12 acetate (Mn12Ac) was able to significantly inhibit the migration and invasion of A549 cells. Western blotting demonstrated that treatment with Mn12Ac was able to upregulate E-cadherin, and downregulate N cadherin and vimentin. It was also identified by a quantitative polymerase chain reaction analysis that Mn12Ac was able to reduce the mRNA expression levels of EMT-associated transcription factors Snail, Slug, Twist-related protein 1 and zinc finger E-box-binding homeobox 1. It was also demonstrated that Mn12Ac was able to reduce the expression levels of Wnt and β-catenin proteins, and suppress the phosphorylation of phosphoinositide 3-kinase (PI3K) and AKT in A549 cells. Notably, it was revealed that Mn12Ac was able to decrease the mRNA and protein expression levels of programmed death ligand-1. Taken together, the results suggested that Mn12Ac is able to inhibit cell migration, invasion and EMT in lung cancer cells by regulating the Wnt/β-catenin and PI3K/AKT signaling pathways. © 2018, Spandidos Publications. All rights reserved.