AbstractInflammation may develop due to internal dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein or external factors in patients with cystic fibrosis (CF). This prospective randomized clinical trial aimed to ascertain the effects of nano‐curcumin as an anti‐inflammatory agent and a CFTR modulator on clinical and inflammatory markers in children with CF. Children with CF were randomly assigned to receive daily curcumin or a placebo for 3 months. The primary outcome measure was to evaluate inflammatory indices, nasopharyngeal swab analysis, and clinical assessments via spirometry, anthropometric measurements, and quality of life (QOL) analysis. Sixty children were included. Intra‐group changes comparison showed that curcumin decreased the level of high‐sensitivity C‐reactive protein (hs‐CRP) (median: −0.31 mg/L, IQR: −1.53 to 0.81;p= .01) and fecal calprotectin level (−29 μg/g, −57.5 to 11.5;p= .03), also increased the level of interleukin (IL)‐10 (6.1 pg/mL, 4.5–9;p= .01). Moreover, curcumin improved the overall QOL and the subscales of the questionnaire. Inter‐group changes comparison depicted the number ofPseudomonascolonies reduced by about 52% in the curcumin group and gained weight by about 16% (p> .05). Nano‐curcumin seems to be considered as an effective nutritional supplement on hs‐CRP, IL‐10, fecal calprotectin levels, and improving QOL in patients with CF.