The emerging Industrial Internet of Things (IIoT) provides industries with an opportunity to collect, aggregate, and analyze data from sensors, including motion control, machine-to-machine communication, predictive maintenance, smart energy grid, big data analysis, and other smart connected medical systems. The physical systems and the cyber systems are organically integrated, forming an interdependent IIoT. This system provides us with enormous advantages, but at the same time, it also introduces the main safety challenges in the design and operation phase. To exploit the security threats of IIoT systems, in this paper, we propose a novel security-by-design approach for interdependent IIoT environments across two different levels, namely, theory modeling and runtime simulation. Our method theoretically analyzes the cascading failure dynamics of the intentional attack network. Simultaneously, we verified the theoretical results through simulations and gave the risk factors that affect the system’s security to mitigate potential security attack threats. Besides, we prove its applicability through comparative simulation experiments to study application environments that rely on IIoT, which shows that our method helps identify risk factors and mitigate IIoT attacks’ mechanism.