Background: Recurrent acute rhinosinusitis (RARS) is characterized by episodic inflammation of the nasal and paranasal sinus mucosa and is frequently triggered by viral infection, with secondary bacterial involvement contributing to symptom persistence and antimicrobial use. Nitric oxide (NO) exhibits antimicrobial and immunomodulatory properties that may be therapeutically advantageous in this setting. This study evaluated the in vitro anti-inflammatory effects of NO generated from a nitric oxide–releasing solution (NORS) and explored the clinical efficacy and safety of a nitric oxide nasal spray (NONS) in adults with RARS. Methods: In vitro experiments assessed NO-mediated cytokine modulation in primary human monocytes and THP-1 cells following lipopolysaccharide stimulation, measuring TNF-α, IL-1β, IL-6, and IL-8 secretion and cytotoxicity across graded NO exposures. Clinically, a multicenter, randomized, double-blind, placebo-controlled phase 2 trial compared the NO generated from NONS to a saline placebo nasal spray in adults with a history of RARS. Participants (68.4% of which were women) initiated a two week (5 doses/day) treatment regimen at the onset of symptoms and were followed for 4 weeks. The primary endpoint was clinical success (cured or much improved) at Day 8; secondary outcomes included quality of life (SNOT-22), intranasal corticosteroid use, antibiotic rescue and safety. Results: In vitro, low NO exposures consistently inhibited TNF-α, IL-1β, and IL-6 secretions from baseline by approximately 40–60%, while IL-8 inhibition was not observed at tolerated non-cytotoxic concentrations. Clinically, 53.6% of NONS-treated participants achieved clinical success at Day 8 compared with 46.3% receiving saline (absolute difference 7.3%; p=0.391), with trends favoring NONS for improved quality of life, lower intranasal corticosteroid use and reduced antibiotic rescue. NONS was well tolerated with adverse events comparable to saline, with no treatment-related serious adverse events observed. Conclusions: NO generated from NORS demonstrates biologically plausible anti-inflammatory activity in monocytic models, and when delivered as NONS shows favorable efficacy trends and good tolerability in RARS. Although statistical significance was not achieved, likely due to the limited evaluable sample size, these findings support further adequately powered trials to define the clinical role of NO-based nasal therapy in RARS management. NONS may have the potential to reduce the duration of each RARS episode, decrease the severity of symptoms of each episode and decrease the number of episodes/year.