<p>Cytokeratin-19 fragment antigen 21-1 (CYFRA21-1) is a clinically important biomarker for the early detection and prognosis of non-small cell lung cancer (NSCLC). Herein, we report a sensitive and label-free electrochemical immunosensor based on a g-C₃N₄/MgO nanocomposite-modified electrode for the selective detection of CYFRA21-1. The g-C₃N₄/MgO nanocomposite served as an efficient sensing interface owing to its large specific surface area, abundant active sites, excellent biocompatibility, and synergistically enhanced electron-transfer properties. The nanocomposite was immobilized on the electrode surface, followed by antibody attachment via a suitable cross-linking strategy and subsequent blocking of non-specific binding sites. The specific antigen–antibody interaction at the electrode surface resulted in a quantifiable decrease in the electrochemical signal as monitored by cyclic voltammetry. Under optimized experimental conditions, the developed immunosensor exhibited a wide linear detection range of 0.1–100 ng mL⁻¹, with a strong linear relationship between peak current and the logarithm of concentration (<i>R</i>² = 0.998). The sensitivity was determined to be 25.3 µA per log (c), and the limit of detection was determined. The lower limit of detection for CYFRA21-1 was calculated to be 1.26 ng mL⁻¹. The sensor also demonstrated a high signal-to-noise ratio (~ 30) indicating excellent detection reliability. Additionally, the suggested platform showed satisfactory reproducibility, long-term stability, and good selectivity against common interfering species. The suggested g-C₃N₄/MgO-based immunosensor has great promise for clinical diagnosis and point-of-care detection of lung cancer biomarkers because of its affordability, simplicity, and sensitivity.</p> Graphical abstract <p></p>