Given the expanding clinical use of orexin-modulating drugs, this study investigated whether orexin agonism or antagonism influences inflammatory responses in vitro and in vivo. PBMCs stimulated with LPS or TNF were treated with orexin agonists or antagonists. In rats, pharmacokinetic/pharmacodynamic studies assessed OXA 17–33 pharmacokinetics and effects on adrenocorticotropin (ACTH) and corticosterone. In collagen-induced arthritis (CIA), rats received OXA 17–33, lemborexant, methylprednisolone, placebo, or no treatment. Disease progression was evaluated using clinical scores, paw width, mechanical allodynia, serum cytokines, and synovial gene and protein expression. OXA 17–33 reduced TNF production in LPS-stimulated PBMCs up to 33.4 ± 12.3% of control (P < 0.001) at a 5 µM concentration. Its pharmacokinetics resembled those of orexin A, with a half-life of 0.48 ± 0.07 h, volume of distribution of 1.84 ± 1.38 L/kg, and clearance of 103.74 ± 45.18 mL/min/kg. Following intravenous administration, OXA 17–33 increased ACTH and corticosterone (57.6 ± 15.0 pg/mL and 256.6 ± 85.9 ng/mL vs 23.9 ± 10.0 pg/mL and 79.4 ± 39.5 ng/mL; both P < 0.05). Subcutaneous dosing significantly increased corticosterone, with a nonsignificant ACTH increase. In CIA, OXA 17–33 produced modest improvements versus placebo, including lower arthritis scores (8.6 ± 0.5 vs 12.0 ± 3.4; P = 0.08), reduced synovial STAT3 expression (P < 0.05), and decreased ERK1/2 and pERK1/2 expression. OXA 17–33 exerts modest anti-inflammatory effects in PBMCs, shows orexin-like pharmacokinetics, and activates the HPA axis. It provided modest prophylactic benefit in CIA, less pronounced than corticosteroid treatment. Lemborexant showed no detrimental effect of OX1R/2 R blockade.