Design and optimization have developed gradually from a methodology for academic attraction into a technology that has made a significant impact on the industrial growth. A careful and well-optimized design of open-channel water ultraviolet (UV) disinfection reactor ensures the achievement of minimum UV dose required, as well as allowing the minimum operational costs. Such UV reactors are mostly utilized in water treatment plants throughout the world to provide the system for disinfecting the drinking water. Yet, at present, lack of rigorous quantitative understanding of behavior in such reactor geometries is shown to limit the versatile and efficient optimization of UV reactor. A new UV reactor design concept is essential that should be able to consider the three significant parameters, namely: uniform UV light propagation within the open-channel UV reactor, providing optimum lamp positioning within the volume of the UV reactor and should allow optimum flow rate of the water. It is approved that computational fluid dynamics (CFD) simulation can be used as a quick and cheap means for design and optimization of water disinfection UV reactor. A novel design and optimization approach which combines CFD modeling, design of experiment (DOE), response surface method (RSM) and goal-driven optimization (GDO) was presented for open-channel water UV disinfection reactor. This methodology includes a heuristic approach from scratch to the final optimal solution. The optimal design variables which have the optimum value of the object functions were identified through proposed methodology. The results showed that the CFD method can be employed for estimation of the optimum design, even though the shape of the open-channel UV reactor is complex. The CFD results reveal that the UV dose distribution and flow of water were largely dependent on the lamp positioning. This paper demonstrates that UV reactor optimization in conceptual design is possible using a commercial CFD package. As a conclusion, the proposed design and optimization technique based on DOE, RSM and GDO could be a suitable technique prior to a final design of open-channel water UV disinfection reactor.