The agreement will see £210m invested into the Derry~Londonderry and Strabane Region City Deal, split equally betweenthe UK government and the NI Executive.
A further £40m investment will be provided by Derry City and Strabane District Council and its delivery partners.
The proposed projects have the potential to deliver an additional 7,000 jobs, according to the UK government.
First Minister Arlene Foster said the signing of the Heads of Terms represents an “important milestone” in the deal.
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“There is a real sense of vibrancy and ambition in the North West,” she added.
“The Executive is working with the UK government, the council and a wide range of stakeholders to turn that potential into reality through collaboration and innovation.
“As the many projects under this project come to fruition, we hope to see benefits not just in Londonderry and Strabane, but right across Northern Ireland.”
Deputy First Minister Michelle O’Neill called the deal a “game-changer for the regional economy, driving growth and creating opportunities for people”.
The investment will support the new Graduate Entry Medical School at Magee while it is hoped the package will see the delivery of up to 10 major projects.
The UK government said the investment will drive growth in output and wages and provide a population boost as further people are attracted to come to the city region to work and study.
Northern Ireland Secretary, Brandon Lewis MP, said: “Today’s announcement is part of the UK government’s commitment to developing and delivering a comprehensive and ambitious set of city deals across Northern Ireland and delivering a stronger economy that works for everyone.”