Whey is a high strength waste product of cheese manufacture. Anaerobic digestion of cheese allows pollution potential reduction and simultaneously energy production. Organic loading rate (OLR) is an important operating variable for anaerobic digestion (AD) process related to system stability, waste treatment capacity and biogas production. The actual OLR depends on the types of wastes (i.e., content of chemical oxygen demand [COD]) fed into a digester. In this paper, the effect of OLR on the AD process of the raw cheese whey in a semi-continuous up-flow system is studied experimentally and with numerical simulations using a simple dynamical model calibrated with experimental data. The digester operation was performed for 90 days, doubling the OLR every 30 days, from OLR of 2.5–10 gCOD L−1 d−1. Experimental results show that the increase in OLR favors the production of biogas. However, the proportion of methane may decrease. The highest methane yield and the most considerable substrate degradation were obtained at OLR of 5 gCOD L−1 d−1 and 10 gCOD L−1 d−1, respectively. The proposed mathematical model is used to describe the dynamic behavior of key variables as COD, volatile fatty acids (VFA) and methane production. A good fit between the variables estimated by the mathematical model and experimental data was obtained, reaching determination coefficients (R2) greater than 0.8. Therefore, this model might be beneficial in predicting the maximum methane production rate and the maximum OLR that could be used without risking the AD process stability.