The human orexin 2 receptor (OX2R) is a G-protein‑coupled receptor (GPCR) that has been implicated in a number of diverse physiological functions. Recent studies have identified a number of functions of the C‑termini of GPCRs. However, the importance of the OX2R C‑terminus in regulating signaling and surface expression remains unclear. In the present study, the function of the OX2R C‑terminus was investigated using three C‑terminal mutants, which were truncated at residues 368, 384 and 414, respectively, and the wild‑type control, which expressed the full‑length OX2R. HEK‑293 cells were transfected with the mutated and control OX2R constructs. ELISA, western blot analysis and calcium assays were used to investigate the effects of the mutations on OX2R function. The present results demonstrated that residues 385‑414 and 415‑444 exhibited a cumulative effect on the surface expression of OX2R. Residues 369‑384 exhibited a significant influence on inositol phosphate production and extracellular signal‑regulated kinase 1/2 phosphorylation. Residues 385‑414 significantly influenced agonist‑induced internalization, whereas residues 369‑384 and 385‑414 significantly influenced Ca2+ release. The results of the present study suggest that the C‑terminus of OX2R is important for its role in various physiological and pathological processes, and may therefore be associated with such disorders as depression and anorexia.