Background: Oncostatin M (OSM) is reported to be involved in many stages of atherosclerosis, including endothelial dysfunction, chronic inflammation, and smooth muscle cell migration. This study explored the effects of OSM on foam cell formation and its corresponding molecular mechanisms. Methods: THP-1 cells were treated with phorbol-12-myristate-13-acetate (PMA) to induce macrophage differentiation and were then exposed to oxidized low-density lipoprotein (ox-LDL). OSM expression was analyzed by quantitative reverse transcription-polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay (ELISA). OSM-specific small interfering RNAs (siRNAs) were transfected into THP-1 macrophages. The effects of OSM silencing were evaluated by Oil Red O staining, ELISA, and Western blotting. Moreover, the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasomes was detected by western blotting and immunofluorescence. Results: OSM was highly expressed in THP-1 macrophages in a time- and dose-dependent fashion. Silencing OSM significantly reduced the total cholesterol content and Oil Red O staining levels in ox-LDL-treated macrophages. Silencing OSM significantly inhibited ox-LDL-induced cytokine release, including TNF-α, IL-1ß, IL-6, and IL-18. Ox-LDL activated p65 and NLRP3, which further induced caspase-1 cleavage, apoptosis-associated, speck-like protein containing a caspase-1 recruitment domain (ASC) upregulation, and gasdermin-D (GSDMD)-N fragmentation. Overexpression of NLRP3 significantly reversed the effects of OSM silencing on ox-LDL-induced foam cell formation and inflammation. Conclusions: OSM was highly expressed in the cell model of atherosclerosis. OSM has a promoting role in ox-LDL-induced foam cell formation and inflammation via the activation of p65-NLRP3 signaling pathways. Silencing OSM may be has benefit in treating atherosclerosis.