A microfluidic chip integrated with a microelectrode and a cathodic photoelectrochemical (PEC) biosensor for the ultrasensitive detection of non-small cell lung cancer cytokeratin fragments based on a signal amplification strategy was designed. The mechanism for signal amplification is developed based on the p-n junction of AgI/Bi2Ga4O9, with dissolved O2 as an electron acceptor to produce the superoxide anion radical (˙O2-) as the working microelectrode. By combining this with a novel superoxide-dismutase-loaded honeycomb manganese oxide nanostructure (SOD@hMnO2) as the co-catalyst signal amplification label, ˙O2- can be catalyzed by SOD via a disproportionation reaction to produce O2 and H2O2; then, hMnO2 is able to trigger the decomposition of H2O2 to generate O2 and H2O. Therefore, the increased O2 promotes the separation of electron-hole pairs via consuming more electrons, leading to an effective enhancement of the cathodic PEC behavior. Under optimum conditions, with the cytokeratin 19 fragments 21-1 (CYFRA 21-1) as the targeted detection objects, the microfluidic cathodic PEC biosensor chip exhibited excellent linearity from 0.1 pg mL-1 to 100 ng mL-1, with a detection limit of 0.026 pg mL-1 (S/N = 3). The exciting thing that this work offers is a new strategy for the detection of other important cancer biomarkers for disease diagnosis and prognosis.