After obtaining her MD and PHD in Switzerland, Ziegler rose to become the head of surgery at a prominent Swiss hospital before pioneering a breakthrough in the field of applied nanobiology that radically improved the treatment of life-threatening illnesses and injuries. It was this expertise that attracted the attention of Overwatch.

Because her parents had been taken by war, Ziegler was opposed to the organization's militaristic approach to keeping global peace. Ultimately, she recognized that Overwatch offered her the opportunity to save lives on a much larger scale. As Overwatch's head of medical research, Angela sought to leverage her work for healing in frontline crises. The result was the Valkyrie swift-response suit, which Ziegler herself piloted on many Overwatch missions.

During her Overwatch years, she once dressed as a witch for Halloween.

Despite her contributions to Overwatch, she was often at odds with her superiors and the organization's overarching aims. One example was the development of the biotic rifle by Torbjorn. Torbjörn provided assurances that the device was only intended for healing, but Ziegler maintained that this was setting Overwatch down a road that could lead to the weaponization of biotic technology, and that she had only conducted research in the field on the condition that it would not be used for offensive purposes.