Quantifying the fate of lipophilic contaminants in lactating cows is the cornerstone for ensuring the chemical safety of dairy products and beef meat. Exploring the effects of cow feeding and physiology on the toxicokinetics of several lipophilic contaminants requires an integrative approach. This study developed and evaluated a mechanistic model (RuMoPOP) of the absorption, distribution, metabolism, and excretion (ADME) of lipophilic contaminant in lactating cows. The model’s rationale relies on the coupling of ADME with physiological sub-models. The ADME sub-model merges the concepts and advantages of former fugacity and physiologically based toxicokinetic models. The physiological sub-model is based on a model that finely describes the dynamics of lipids in the digestive contents, body, and milk, depending on the milk production level (from a low-yielding suckler cow to a high-yielding dairy cow). The model was fitted to toxicokinetic data from two dairy cow experiments for polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans. Model performances for predicting milk accumulation and depuration kinetics were judged satisfactory, with an average root mean square error relative to the observed mean of 27%. The model makes it possible to predict the variability in accumulation and depuration kinetics, depending on contaminant lipophilicity, hepatic clearance rate, and diet lipid content and digestibility, over the whole lifespan of low- and high-yielding cows. The RuMoPOP model is a valuable tool for exploring the complex interplay between lipophilic contaminant properties and cow physiology and ultimately contributes to the chemical safety of diverse dairy and beef production systems towards legacy and emerging lipophilic contaminants.