Understanding the interactions of guest molecules like proteins and nanoparticles with microgels is fundamental for using microgels as nanocarriers. However, understanding and predicting the system properties becomes increasingly difficult as the systems become more complex. In this study, we systematically investigated the uptake of these guest molecules in a pH-responsive polyelectrolyte microgel modeled as a bead-spring network using Monte Carlo simulations. To narrow down the complexity of the systems, we modeled the guest molecules as simple charged beads. The simulations included the variation of (i) guest molecule charge, (ii) size, and (iii) number, as well as the influence of (iv) the addition of salt. The effect of these parameters on the ionization, swelling, and guest molecule uptake was investigated. The uptake of guest molecules with higher charges enhanced the ionization of the microgel at low pH. The strongest effect was observed for beads with charge z = +15. For higher guest molecule charges, the polymer chains could not fully wrap around the guest molecules, to provide enough microgel charges to fully compensate for the repulsive interactions between the guest beads. In general, the uptake of guest molecules leads to a collapse of the microgel due to attractive electrostatic interactions. With the increasing size of the guest molecules, their excluded volume increases, and the microgel swells with their uptake. Adding monovalent salt slightly decreases the uptake at low ionization of the network due to electrostatic screening. The presence of salt ions with higher valency further decreases the uptake of guest molecules into a fully ionized microgel.