After learning that Daisy Johnson and Jemma Simmons had infiltrated the Framework, Aida designed a plan to keep them from completing her plans. With the assistance of Melinda May and a reluctant Alphonso Mackenzie, she tricked Johnson into admitting her allegiance to S.H.I.E.L.D.. As a result, Johnson was arrested and imprisoned at the Triskelion. However, during the Infiltration into the HYDRA Enlightenment Cultivation Center, May discovered that HYDRA was forcefully indoctrinating children. Moreover, while she had been sent to kill the Patriot, the S.H.I.E.L.D. leader eventually saved her life by keeping the quarantine building from collapsing. As a result, May questioned her allegiance to HYDRA and decided to release Johnson.
After returning from her mission, Melinda May sneaked a Terrigen Crystal in Daisy Johnson's cell. Although Johnson was heavily wounded after The Doctor interrogated her, Johnson proudly stated that she was an Inhuman and that she could bring the Triskelion down. Upon hearing this, May shattered the Crystal and triggered Johnson's Terrigenesis, which ended with Johnson emerging fully recovered out of her husk with a quake. The process drew attention of a HYDRA guard who tried to call for reinforcements before being knocked out by May. Johnson took his gun and the pair left the cell.
May and Johnson made their way through the Triskelion, killing the HYDRA agents who were trying to stop them. They reached a corridor where an elevator could lead them to the garage, but upon arriving in front of it, Madame Hydra came out of it with two armed guards who ordered them to put down their weapons, which they did. Madame Hydra confronted May about her behavior, telling her that her prisoners seemed to eventually come back to their true nature. However, she did not mention Johnson, who used her newly recovered powers to throw Madame Hydra out of the building. The HYDRA leader broke the windows and hardly fell on the ground, which broke her spine. May and Johnson then left the Triskelion.
HYDRA immediately sent troops in the streets to find the two women. On their way, May told about the events of the Infiltration into the HYDRA Enlightenment Cultivation Center who had her changing sides. Although Johnson was shaken upon learning the Patriot's death, they carried on their escape and made their way to a S.H.I.E.L.D. rendezvous point. They discovered that HYDRA had disclosed their identities to the public, especially through Sunil Bakshi's show The Bakshi Report, and stole a car to go faster.
May and Johnson finally reached the meeting point. While they were negotiating with the S.H.I.E.L.D. agent, they were found by HYDRA soldiers who shot at them and hurt the S.H.I.E.L.D. agent. Using her powers, Quake managed to get rid of their opponents and the three hid into the building. May and Johnson discussed their options before another HYDRA squad sent by Alistair Fitz broke into the facility. They managed to take two operatives down but where held at gunpoint by another. Fortunately, Phil Coulson, Alphonso Mackenzie and Burrows, who had been warned by the agent responsible of the meeting point, arrived in time to rescue them. Although Mackenzie was ready to kill May as well because of what she had done to his daughter, Johnson and Coulson convinced him otherwise. Afterwards, Burrows led them to a secret exit and all of them went to the Playground.
After being rescued by S.H.I.E.L.D. and taken to the Playground, Melinda May decided to join the resistance against HYDRA. She took care of the refugees and provided S.H.I.E.L.D. with the footage taken by her body cam during the Infiltration into the HYDRA Enlightenment Cultivation Center in order to make amends for the wrongs she had done. This enabled S.H.I.E.L.D. to create a subversive broadcast meant to trigger a massive rebellion against HYDRA.
Following her serious injuries, Madame Hydra urged her lover The Doctor to complete the designs of the Project Looking Glass so that she would be able to get a new human body, which she described as the only way of saving her.