A novel methodology has been developed to design an optimum heterogeneous catalytic reactor, by considering non-uniform catalyst pellet under shell-progressive catalyst deactivation. Various types of non-uniform catalyst pellets are modelled in combination with reactor design. For example, typical non-uniform catalyst pellets such as egg-yolk, egg-shell and middle-peak distribution are developed as well as step-type distribution. A progressive poisoning behavior is included to the model to produce correct effectiveness factor from non-uniform catalyst pellet. As opposed to numerical experiment with limited type of kinetic application to the model in the past, this paper shows a new methodology to include any types of kinetic reactions for the modeling of the reactor with non-uniform catalyst pellet and shell-progressive poisoning. For an optimum reactor design, reactor and catalyst variables are considered at the same time. For example, active layer thickness and location inside pellet are optimised together with reactor temperature for the maximisation of the reactor performance. Furthermore, the temperature control strategy over the reactor operation period is added to the optimization, which extends the model to three dimensions. A computational burden has been a major concern for the optimization, and innovative methodology is adopted. Application of profile based synthesis with the combination of SA (Simulated Annealing) and SQP (Successive Quadratic Programming) allows more efficient computation not only at steady state but also in dynamic status over the catalyst lifetime. A Benzene hydrogenation reaction in an industry scale fixed-bed reactor is used as a case study for illustration.