Measuring CA 19-9 antigen level is critical for early diagnosis of pancreatic cancer, monitoring the treatment process, and predicting disease recurrence. The purpose of this research is to assess the application of novel fewlayered TiS3 nanoribbons material as a channel material in electrolyte-gated field-effect transistor immunosensor for rapid detection of CA 19-9 antigen as a cancer marker. Accordingly, TiS3 nanoribbons were produced through liquid-phase exfoliation of as-synthesized TiS3 whiskers in N, N-dimethylformamide. Then, dispersed TiS3 nanoribbons were drop cast onto the FET surface to form an active channel material between source and drain electrodes. Subsequently, the channel surface was modified by utilizing 1-naphthylamine (NA) and glutaraldehyde (GA) to strengthen the binding of monoclonal antibody 19-9 to TiS3 nanoribbons. Spectroscopic and microscopic methods were utilized for comprehensive characterizations. Electrical characterization of electrolyte-gated TiS3 nanoribbons field-effect transistor represented a depletion-mode n-type behavior with field-effect mobility of 0.059 cm2/Vs, current on/off ratio of 10.88 and subthreshold swing (SS) of 450.9 mV/ decade. With increasing in CA 19-9 antigen concentration from 1.0 × 10− 12 U/mL to 1.0 × 10− 5 U/mL, a decrease in the drain current occurred with high sensitivity of 0.04 μA/decade and a detection limit of 1.3 × 10− 13 U/mL. Additionally, the proposed TiS3 nanoribbons FET immunosensor exhibited outstanding selectivity, and its good performance was compared with an enzyme-linked immunosorbent assay (ELISA) for spiked real human serum samples. The good and satisfactory obtained results of the proposed immunosensor suggest that the developed platform can be a superb candidate for cancer diagnosis and therapeutic monitoring.