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Objective To investigate the role of autophagy in hypoxia-activated CaSR(calcium-sensing receptor,CaSR) in mediating migration of A549 cells. Methods A549 cells in the logarithmic growth phase were randomly divided into control group(N), hypoxia group (H), hypoxia agonist group (H+Gd), hypoxia inhibitor group (H+NPS), and autophagy pathway inhibitor group (H+Gd+3-MA).Western blot was used to detect the expression of CaSR and autophagy protein (Beclin-1) in the cells; Cell scratch experiment was used to detect migration of A549 cells; Transwell assay was applied to evaluate the invasion of A549 cells. Results Hypoxia resulted in increased CaSR expression in A549 cells (P＜0.05), a decreased expression of autophagic effector protein Beclin-1(P＜0.05), increased the percentage of cell healing per unit time (P＜0.05), and the number of cell invasion-permeable membranes (P＜0.05).GdCl3 strengthened the effect of hypoxia, while NPS2390 did weaken the effect of hypoxia. On the basis of hypoxia and GdCl3 conditions, 3-MA further increased the expression of metastasis related indicators of A549 cells, but not the autophagy related indicators. Conclusions CaSR activation promotes migration and invasion of A549 cells by down-regulating autophagy.