Background/Objectives: Long COVID is characterised by persistent symptoms such as fatigue, pain, cognitive impairment, sleep disturbances, and reduced quality of life (QoL) following SARS-CoV-2 infection. Proposed mechanisms include persistent immune activation, chronic inflammation, oxidative stress, endothelial dysfunction, mitochondrial disturbances, and virus-induced cellular senescence. Current management is largely supportive, highlighting the need for complementary strategies targeting these pathways. Natural polyphenols such as quercetin and curcumin possess anti-inflammatory, antioxidant, immunomodulatory, and potential senolytic properties that may modulate multiple pathways implicated in Long COVID. This study aimed to explore the potential complementary effects of oral quercetin-curcumin co-supplementation, administered alongside usual symptomatic management, in adults with persistent Long COVID symptoms. Methods: This single-centre, open-label, single-arm, pragmatic exploratory study enrolled 15 adults with Long COVID in an outpatient real-life clinical practice setting. Participants received a nutraceutical formulation containing quercetin (65 mg) and Curcuma longa extract standardised to provide 42 mg curcumin (Nasafytol®), administered as two capsules twice daily for 8 weeks in addition to standard care. The primary endpoint was change in overall symptom burden assessed using the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS). Secondary outcomes included fatigue (Fatigue Severity Scale, FSS), pain (Brief Pain Inventory-Short Form, BPI-SF), cognitive function (Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, PROMIS-CF-8a), mood (Hospital Anxiety and Depression Scale, HADS), sleep quality (Pittsburgh Sleep Quality Index, PSQI), autonomic symptoms (Composite Autonomic Symptom Score-31, COMPASS-31), and health-related QoL (Medical Outcomes Study 36-Item Short-Form Health Survey, SF-36). Results: After 8 weeks, overall symptom burden significantly decreased (C19-YRS median 50 to 32; q = 0.018). Significant reductions were observed in patient-reported fatigue (q = 0.006), pain severity and interference (q = 0.006), and improved physical health-related QoL (SF-36 PCS; q = 0.025). Numerically favourable changes were also observed in cognitive function, anxiety, sleep quality, and autonomic symptoms, although these did not reach statistical significance. The supplementation was generally well tolerated with no serious adverse events. Conclusions: Quercetin-curcumin co-supplementation was associated with lower patient-reported symptom burden, fatigue, and pain and better physical health-related QoL after 8 weeks of supplementation in adults with Long COVID. These observed findings represent treatment-associated changes within this uncontrolled exploratory study and should be interpreted cautiously. Further evaluation in adequately powered randomised placebo-controlled trials is warranted. Trial registration: ClinicalTrials.gov (ID NCT06974058).
