Along with the fourth industrial revolution, industrial automation systems are evolving into a multi-tier end-edge computing architecture. Edge controllers, which are equipped with a larger computing capacity compared to local controllers, can communicate with local plants over mainstream wireless networks such as WirelessHART, Wi-Fi, and cellular networks. Well-known challenges induced by networks, such as uncertain time delays and packet drops, have been intensively investigated from various perspectives: control synthesis, network design, or control and network co-design. The status quo is that the industry remains hesitant to close the loop between the edge controller and the actuation side due to safety concerns. This work offers an alternative perspective to address the safety concern, by exploiting the design freedom of an end-edge computing architecture. Specifically, we present a smart actuation framework, which deploys (1) an edge controller, which communicates with physical plant via wireless network, accounting for optimality, adaptation, and constraints by conducting computationally expensive operations; (2) a smart actuator, which is co-located with the physical plant on the end tier and executes a local control policy, accounting for system safety in the view of network imperfections, (3) the end-edge control co-design strategies and cooperation logic for both performance and stability. For certain classes of plants, semi-globally asymptotic stability of the resulting end-edge control systems is established when the edge controller is the model predictive control (MPC), or policy iteration-based learning control. We also provide an adaptation strategy for the end-edge control systems facing model parameter mismatches when the edge controller employs reinforcement learning. Extensive simulations demonstrate the advantages of the proposed end-edge co-design and cooperation procedures. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —Edge computing is gaining momentum in areas that require low latency and high efficiency, i.e., mobile computing, video analytics, and autonomous driving. Industrial automation systems are also evolving into a multi-tier end-edge computing architecture. It pays obvious dividends to leverage the cooperation between end and edge, benefiting from fast and reliable communication on the end side, and powerful computation capacity on the edge side. The current end-edge cooperation focuses on how to partition tasks and offload computation resources in order to minimize delay and energy consumption, as well as how to balance the tradeoff between them. However, the impacts of end-edge cooperation on the safety, optimality, and cost of industrial automation have not been systematically studied. This paper aims to tailor end-edge cooperation in a smart actuation framework, for industrial automation to reconcile the above aspects by leveraging co-design of end and edge controllers and their switching logic. Extensive pure and semi-physical simulations demonstrate the advantages in performance and system stability of the proposed end-edge co-design and cooperation procedures.