True metal nanoparticle (NP) analysis directly in solid biomatrices, involving sizing and counting, using the recently introduced laser ablation-single particle-inductively coupled plasma mass spectrometry (LA-SP-ICPMS) technique, is prone to produce erratic results when the instrument is not set up correctly and non-optimal operational conditions are used. This work offers deeper insights into the analysis of NPs by LA-SP-ICPMS, based on modeling the chain of events from NP release to LA cell washout to ICPMS detection as a function of the biomatrix characteristics, instrumental specifications and variable operational settings. By processing the computational data via an “outlier” filter to differentiate between metal NPs and dissolved metal, guidelines were established for instrumental setup and operation, assuming the measurement of homogeneously distributed metal NPs and dissolved metal, and using a laser fluence ≤1 J cm⁻² to circumvent NP degradation. An online app (http://193.2.14.6:9988/webapps/home/) was developed, based on the model, to predict the SP analysis capabilities of arbitrary LA-ICPMS setups using a custom detectability criterion.