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Resistive pulse sensing (RPS) measurements of nanoparticle translocation have the ability to provide information on single-particle level characteristics, such as diameter or mobility, as well as ensemble averages. However, interpreting these measurements is complex and requires an understanding of nanoparticle dynamics in confined spaces as well as the ways in which nanoparticles disrupt ion transport while inside a nanopore. Here, we combine Dynamic Monte Carlo (DMC) simulations with Machine Learning (ML) and Poisson–Nernst–Planck calculations to simultaneously simulate nanoparticle dynamics and ion transport during hundreds of independent particle translocations as a function of nanoparticle size, electrophoretic mobility, and nanopore length. The use of DMC simulations allowed us to explicitly investigate the effects of Brownian motion and nanoparticle/nanopore characteristics on the amplitude and duration of translocation signals. Simulation results were verified with experimental RPS measurements and found to be in quantitative agreement.