AbstractIn this paper, the formulation, calibration, and validation of hybrid and coupled models for the design of upflow anaerobic filters in multiple separated stages were developed for organic matter removal from sanitary landfill leachates. Three novelties were presented, the type of reactor, design models, and kinetic coefficients. The upflow anaerobic filters were separated into two and three stages identified as UAF‐2SS (DI‐FAFS, in Spanish) and UAF‐3SS (TRI‐FAFS, in Spanish). The formulation, calibration, and validation of mathematical structures of hybrid models and five coupled models are proposed for each reactor. The hybrid models are based on the law of mass conservation, with the organic matter transformation component within the UAF‐2SS and UAF‐3SS reactors, being estimated from empirical equations that have been tested in aerobic culture reactors, adapted to the experimental factors, including among these, those under a non‐stationary—advective conditions based on Velz's Law, Phelps's Law, and Monod's equation. The coupled models combine the components of the molecular transport by biosorption and molecular diffusion processes, with adaptations of the Stack's equation and Fick's Law, as well as transformation of organic substrates by biomass, whose kinetic coefficients contribute to explain the fraction, in which, the processes of mobility and biochemical transformation of the organic matter are occurring in the biomass within the bioreactors.