One big obstacle for a redox mediator (RM)-based Li–O2 system is the redox shuttling between the diffusible RM+ and Li anode, leading to the unexpected RM degradation and continuous deterioration of Li anode, which inevitably results in a low energy efficiency and a poor cycling stability for the Li–O2 battery. Here, InBr3 as a self-defensed RM is firstly introduced into Li–O2 batteries, which can lower the cell overpotential and thus improve the cycling performance. Moreover, due to the In3+ existence, an In-rich composite protective layer can be in situ generated on the Li anode, which contributes to suppressing the redox shuttling, improving the interface stability of Li and electrolyte, and inhibiting the dendrite formation. This work gives an insight into the development of self-defensed RM and the protection of the Li anode for Li–O2 batteries.