River chief system is a regional management policy for environmental protection. Joint protection and management at basin level is still a challenge and shortage in the implementation of the river chief system. With Chishui River, a representative inter-provincial river in the Changjiang River Basin as an example, we expound the key issues in the eco-environment protection of Chishui River, and make a review on the practices of applying river chief system. On such basis, we summarize the experiences and lessons learned from the protection and management of Chishui River according to the major tasks of river chief system. Moreover, we put forward policy measures for the joint protection and management in the following aspects: promoting the overall planning and legislation for basin comprehensive management, strengthening interdepartmental cooperation and joint law enforcement, standardizing cross-regional sectional monitoring and assessment, tightening basin water allocation and scheduling, and improving financial support and encourage. The present research will provide policy support for basin integrated protection and management for other inter-provincial rivers elsewhere in China.