Background/Aim:　Spalt-like　transcription　factor　4　(SALL4),　as　a　proto-oncogene,　is　expressed　in　various　tumors　and　correlates　with　poor　prognosis　of　patients.　Entinostat,　a　histone　deacetylase　(HDAC)　inhibitor,　has　emerged　as　a　potentially　promising　anti-cancer　drug.　This　study　aims　to　explore　the　biological　role　and　underlying　mechanism　of　SALL4　targeting　by　entinostat　in　gastric　cancer.　Materials　and　Methods:　Online　databases　were　used　to　exam　the　link　between　SALL4　and　prognosis.　We　tested　the　biological　roles　of　SALL4　in　gastric　cancer　cells.　Cell　viability　and　growth　were　analyzed　using　the　Cell　Counting　Kit-8　(CCK-8)　assay　and　clone　formation　assay.　Cell　migration　was　assessed　using　the　wound　healing　assay.　The　effects　of　entinostat　on　gastric　cancer　cell　lines　were　measured　by　the　CCK-8　assay,　clone　formation　assay,　wound　healing　assay　and　transwell　assay.　Epithelial-mesenchymal　transition　(EMT)　signaling　pathways　were　detected　by　western　blot.　Results:　SALL4　expression　was　upregulated　in　gastric　cancer　tissues　and　positively　correlated　with　tumor　stage　and　prognosis　of　patients　by　TCGA　dataset　analysis.　Knockdown　of　SALL4　by　siRNA　inhibited　the　proliferation　and　migration　of　gastric　cancer　cells.　In　contrast,　SALL4　overexpression　by　stably　transfecting　a　SALL4-expressing　plasmid　promoted　the　proliferation　and　invasiveness　of　gastric　cancer　cells　in　vitro　through　alteration　of　EMT　-related　genes.　In　addition,　entinostat,　a　HDAC　inhibitor　targeting　SALL4,　could　suppress　the　proliferation,　migration,　and　invasion　of　gastric　cancer　cells　via　regulating　expression　of　EMT-associated　proteins.　Conclusion:　SALL4　may　be　a　new　therapeutic　target　for　the　treatment　of　gastric　cancer,　and　entinostat　is　a　potential　novel　agent　for　the　treatment　of　gastric　cancer　partially　by　targeting　SALL4.