Blake, who has been chief executive of the NUS for three years, will on 3 October take up his new role at the community interest company that trains people to help those around them manage their mental health.
He said he was thrilled to be returning to the health sector after a nine-year stint at sexual health charity Brook prior to joining the NUS.
"This is a job I know I will be passionate about," he said. "Our challenge at MHFA England is to achieve parity with physical first aid and the proposed legislative changes we are campaigning for will go a long way to enabling this to happen".
Blake said leading the NUS "isn't always straightforward", but he had had a great time working with three different presidents.
He said he would leave this month and have a holiday before starting his new role.
Peter Robertson, his deputy, will take charge until the NUS decides on a succession plan.
MHFA England, which was set-up as a community interest company in 2009, aims to train one in 10 people in mental health first aid.
It is based in London, employs about 60 staff and had income of £2.6m in the 2016/17 financial year.
Since founding member Poppy Jaman stepped down as chief executive in March, the organisation has operated a joint leadership model with Fionuala Bonnar, chief operating officer, Caroline Hounsell, director of partnerships and product development, and Eleanor Miller, director of marketing and communications, in charge.
Professor Mark Watson-Gandy, chair of MHFA England, said: "Simon has an excellent track record of working in senior strategic roles within the not-for-profit and commercial sectors.
"We are confident he will bring formidable strategic vision and operational energy to MHFA England."