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Objective The aim of this research was to systematically investigate the effects of endothelial mesenchymal transition (EndMT) induced by hypoxia on the skin microvascular remodeling of systemic sclerosis (SSc) and the underlying mechanism. Methods Skin tissues from SSc patients and controls were collected for isobaric tags for the relative and absolute quantification (iTRAQ)-based proteomics and immunohistochemical test. Human microvascular endothelial cell line-1 (HMEC-1) cultured in hypoxic or normal conditions was treated by tamoxifen or bevacizumab. Results The iTRAQ-based proteomics indicated a significantly upregulated hypoxia-inducible factor-1 (HIF-1) signal in SSc samples. The immunohistochemical results demonstrated the significant downregulation of CD31, the positive staining of α-smooth muscle actin (α-SMA), HIF-1α, and vascular endothelial growth factor (VEGF-a) in SSc skin tissues, compared with control samples. Consistent with these observations, HMEC-1 cells cultured under hypoxic conditions exhibited a significant decrease in CD31 and VE-cadherin expression, alongside a marked increase in the expression of α-SMA and fibronectin, as well as a distinct upregulation of HIF-1α and VEGF-a, when compared with those under normal conditions. It is noteworthy that the inhibition of HIF-1α by tamoxifen effectively downregulated the hypoxic induction of VEGF-a and α-SMA while rescuing the hypoxic suppression of CD31. In addition, the VEGF-a inhibitor bevacizumab treatment had the same effect on the hypoxic expression of α-SMA and CD31, as a tamoxifen intervention, but did not reduce HIF-1α. Conclusion These results suggest that the HIF-1α/VEGF signaling pathway can have a critical role in mediating the effect of hypoxia-induced EndMT on the skin microvascular remodeling of SSc.