Quantifying the fate of lipophilic contaminants in lactating cow is the cornerstone for ensuring the chemical safety of dairy products and beef meat. Exploring the effects of cow feeding and physiology on the toxicokinetic of several lipophilic contaminants require an integrative approach. Here the mechanistic RuMoPOP model of the lipophilic contaminant absorption, distribution, metabolism, and excretion (ADME) in lactating cows is introduced. The rationale of the RuMoPOP model relies on the coupling of ADME with physiological sub-models. The ADME sub-model merges the concepts and pros of former fugacity- and physiologically-based toxicokinetic models. The physiological sub-model is based on a model that describes finely the dynamics of lipids in the digestive contents, body and milk depending on the milk production level (from low-yielding suckler cow, up to 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 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- to high-yielding cows. The RuMoPOP model is a valuable contribution to explore 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.