Graphene has attracted enormous research interest due to its extraordinary material properties. Process control to achieve high-quality graphene is indispensable for graphene-based applications. This research investigates the effects of process parameters on graphene quality in a low-pressure chemical vapor deposition (LPCVD) graphene growth process. A fractional factorial design of experiment is conducted to provide understanding on not only the main effect of process parameters, but also the interaction effect among them. Graphene quality including the number of layers and grain size is analyzed. To achieve monolayer graphene with large grain size, a condition with low CH4–H2 ratio, short growth time, high growth pressure, high growth temperature, and slow cooling rate is recommended. This study considers a large set of process parameters with their interaction effects and provides guidelines to optimize graphene growth via LPCVD focusing on the number of graphene layers and the grain size.