This paper presents specific noise minimization strategies to be adopted in silicon–cell interfaces. For this objective, a complete and general model for the analog processing of the signal coming from cell–silicon junctions is presented. This model will then be described at the level of the single stages and of the fundamental parameters that characterize them (bandwidth, gain and noise). Thanks to a few design equations, it will therefore be possible to simulate the behavior of a time-division multiplexed acquisition channel, including the most relevant parameters for signal processing, such as amplification (or power of the analog signal) and noise. This model has the undoubted advantage of being particularly simple to simulate and implement, while maintaining high accuracy in estimating the signal quality (i.e., the signal-to-noise ratio, SNR). Thanks to the simulation results of the model, it will be possible to set an optimal operating point for the front-end to minimize the artifacts introduced by the time-division multiplexing (TDM) scheme and to maximize the SNR at the a-to-d converter input. The proposed results provide an SNR of 12 dB at 10 µV_RMS of noise power and 50 µV_RMS of signal power (both evaluated at input of the analog front-end, AFE). This is particularly relevant for cell–silicon junctions because it demonstrates that it is possible to detect weak extracellular events (of the order of few µV_RMS) without necessarily increasing the total amplification of the front-end (and, therefore, as a first approximation, the dissipated electrical power), while adopting a specific gain distribution through the acquisition chain.