The detection of circulating protein (CP) is very important for the diagnosis and therapeutics of cancer. Conventional techniques based on a specific antibody-antigen interaction are still lacking because of a shortage of cost effectiveness, complicated sandwich structure and tagging process, and inconsistent detection of CP due to the inherent instability of antibodies. Herein, we demonstrate a hybrid device consisting of two-dimensional (2D) nanoscale molybdenum disulfide (MoS2) field-effect transistor (FET) with an amyloid-β1-42 (Aβ1-42) functionalized surface, which amplifies electric signals of the FET in order to detect matrix metalloproteinase-9 (MMP-9), which is a certain type of CP that degrades Aβ1-42. With the hybrid device, we detected the concentrations of MMP-9 in the range from 1 pM to 10 nM. Moreover, using tapping-mode atomic force microscopy and Kelvin probe force microscopy, we verified that the signal amplification corresponding to the MMP-9 concentrations was caused by the reduced length and the decreased surface potential of degraded Aβ1-42 due to MMP-9. The hybrid device studied in this paper can be very useful for monitoring MMP-9 activity, as well as serving as a sensing platform for the electrical signal amplification of 2D MoS2 FET-biosensors.