Adsorption-based microfluidic sensors are promising tools for biosensing. Advanced mathematical models of time response and noise of such devices are needed in order to improve the interpretation of measurement results, and to achieve the optimal sensor performance. Here the mathematical models are presented that take into account the coupling of processes that generate the sensor signal: adsorption–desorption (AD) of the target analyte particles on the heterogeneous sensing surface, and mass transfer (MT) in a microfluidic chamber. The response kinetics and AD noise (which determines the ultimate sensing performance) of protein biosensors are analyzed, assuming practically relevant analyte concentrations, sensing surface areas and MT parameters. The condition is determined under which MT significantly influences the sensor characteristics relevant for reliable analyte detection and quantification. It is shown that the development of improved mathematical models of sensor temporal response and noise can be used as one of strategies for achieving better sensing performance.