Aim Accumulating evidence suggests that orexin signaling is involved in the regulation of blood pressure and cardiovascular function. However, the underlying mechanisms are not clear. Here we test the hypothesis that upregulated orexin A signaling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating expression of proinflammatory cytokines (PICs). Methods In vivo sympathetic nerve recordings were performed to test the impact of PVN orexin signaling on sympathetic outflow in Sprague‐Dawley (SD) rats. Real‐time PCR was carried out to assess effects of central administration of orexin A on PVN PICs expression in SD rats. To test whether orexin A induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R expressing PC12 (PC12‐OX1R) cells were incubated with different dose of orexin A, then PICs mRNA and immunoreactivity were measured. Results Orexin A microinjection (25 pmol) into the PVN significantly increased splanchnic SNA (93.5%) and renal SNA (83.3%) in SD rats, and these increases were attenuated by OX1R antagonist SB408124. Intracerebroventricular injection of orexin A (0.2 nmol) into SD rats increased mRNA levels of PICs including IL1‐β (2.7‐fold), IL6 (1.7‐fold) and TNF‐α (1.5‐fold), as well as Fra1 (1.6‐fold) in the PVN. Orexin A treatment in PC12‐OX1R cells resulted in a dose‐ and time‐dependent increase in the expression of PICs and Fra1, a subunit of AP1 transcriptional factor. The increase in the PICs was blocked by AP1 blocker curcumin. Conclusion PVN orexin system activation is involved in SNA regulation maybe through triggering AP1‐PICs pathway. This article is protected by copyright. All rights reserved.