Objective To investigate the effect and mechanism of M2 macrophages-derived small extracellular vesicle (M2-sEV) on injury of H9C2 cardiomyocytes induced by chronic intermittent hypoxia (CIH). Methods Interleukin-4(IL-4) was used to induce the polarization of RMa-bm macrophages to M2-type. The mRNA expression levels of M2-type markers CD206 and arginase-1（Arg-1） were detected by quantitative reverse transcription PCR (qRT-PCR). M2-sEV were extracted and identified. The signature proteins CD9, CD63 and CD81 of M2-sEV were detected by Western blotting(WB). H9C2 cells were randomly divided into control（CON） group, CIH group and CIH+M2-sEV group. CCK8 was used to detect cell viability, and qRT-PCR and WB were respectively used to detect mRNA and protein expression of hypoxia-inducible factor-1α (HIF-1α）, IL-6、tumor necrosis factor-α（TNF-α）、transforming growth factor-β（TGF-β） and apoptotic factors(cleaved caspase-3、cleaved caspase-9、Bcl-2、Bax) as well as endoplasmic reticulum stress factors (IRE1α、XBP1、ATF6、GRP78). Results M2-type macrophages were polarized successfully and M2-sEV were extracted successfully. CCK8 showed that M2-sEV increased the proliferation activity of H9C2 cardiomyocytes under CIH. Compared with the CON group, the expression level of HIF-1α, inflammatory factors (IL-6,TNF-α,TGF-β), pro-apoptotic proteins(cleaved caspase-3, cleaved caspase-9, Bax) and endoplasmic reticulum stress factors (IRE1α, XBP1, ATF6, GRP78) were significantly increased in the CIH group(P<0.05) in both mRNA and protein level. The protein level of Bcl-2 in the CIH group was decreased, and the ratio of Bax/Bcl-2 was increased in the CIH group (P<0.05). However, after co-incubating with M2-sEV, the expressions of HIF-1α, inflammatory factors, pro-apoptotic proteins and endoplasmic reticulum stress factors in CIH group were significantly decreased (P<0.05), and the expression of Bcl-2 and the ratio of Bax/Bcl-2 were also decreased (P<0.05). Conclusions M2-sEV can alleviate the injury of H9C2 cell induced by CIH, which is related to the downregulation of endoplasmic reticulum stress, inhibition of inflammation and reduction of apoptosis.