Vasculogenic mimicry (VM) is associated with aggressive cancer cells. Salvianolic acid A (Sal-A), an antioxidant and anti-inflammatory agent, has bioactive properties from Salvia miltiorrhiza Bunge. Current investigation aspired to explore the activity of Sal-A in the VM formation of non-small cell lung cancer (NSCLC) and the mechanism underling this function. The CCK8, the scratch and boyden chemotaxis assay were presented to describe NSCLC cells viability, migration and invasion capabilities, respectively. The protein expression was verified by western blotting. In this report, Sal-A caused a reduction in viability, metastasis and capillaries structure formation of NSCLC cells. Additionally, Sal-A markedly prevented the key VM related proteins, containing EphA2, VE-cadherin and MMP2. Besides, Sal-A significantly diminished p-PI3K, p-Akt and p-mTOR level in NSCLC cells. More importantly, SC79 pretreatment reversed Sal-A inhibits NSCLC cells viability, metastasis and VM formation. These data exhibit that Sal-A could block VM network formation in NSCLC cells through modulating the PI3K/Akt/mTOR signalling pathway. © 2021 John Wiley & Sons Australia, Ltd.