In a petroleum cyber-physical system (CPS), interwell connectivity estimation is critical for improving petroleum production. An accurately estimated connectivity topology facilitates reduction in the production cost and improvement in the waterflood management. This paper presents the first study focused on computer-aided design for a petroleum CPS. A new CPS framework is developed to estimate the petroleum well connectivities. Such a framework explores an innovative water/oil index integrated with the advanced cross-entropy optimization. It is applied to a real industrial petroleum field with massive petroleum CPS data. The experimental results demonstrate that our automated estimations well match the expensive tracerbased true observations. This demonstrates that our framework is highly promising.