Long-term exposure to glucocorticoids (GCs) downregulates SSTR2 expression in corticotroph tumors, limiting the efficacy of octreotide (OCT) in the treatment of Cushing disease (CD). In AtT20 cells, dexamethasone (DEX) increased the expression of miR-375, which has a seed sequence for Ssrt2, supporting the hypothesis that excessive GC exposure can lead to epigenetic SSTR2 downregulation. The current study aims to evaluate miR-375 levels by reverse transcription quantitative polymerase chain reaction in sera from patients with CD, human corticotroph pituitary tumors, normal pituitaries, and AtT20/D16 and GH3 cells, and miR-375 impact on SSTR2 expression in AtT20/D16 and human corticotroph pituitary tumors. SSTR2 protein expression and localization were evaluated by WB and IF in AtT20/D16 and human primary cultures. Proliferation assay and flow cytometry were assessed to investigate the impact of miR-375 regulation on OCT treatment in AtT20/D16. miR-375 levels were higher in sera from patients with CD than in healthy subjects, and in human corticotroph pituitary tumors than in normal pituitaries. AtT20/D16 and GH3 exhibited an inverse expression pattern, with SSTR2 mRNA at low levels and miR-375 at high levels in AtT20/D16 and an opposite expression pattern in GH3. DEX treatment significantly reduced SSTR2 gene expression, while miR-375 inhibition significantly increased SSTR2 membranous protein expression in AtT20/D16 and primary cultures. Receptor internalization appeared stronger when OCT was combined with miR-375 inhibitor. The decreased cell proliferation induced by OCT was potentiated by miR-375 inhibition, increasing cells in early and late apoptosis, by inducing PARP, Caspase3, and ERK1/2 phosphorylation. In conclusion, SSTR2 protein expression can be epigenetically downregulated by GC-induced miR-375 expression, at least partially influencing OCT action in corticotroph pituitary tumors.