The Great Fire of London devastated the city, creating a massive need for reconstruction. This event provided Hooke with a significant opportunity to apply his engineering and architectural skills.

Hooke was appointed as one of the city surveyors, working alongside Christopher Wren and others to oversee the rebuilding of London. This role involved surveying damaged properties, planning new streets, and designing new buildings.

Hooke designed numerous buildings in London, although many were later destroyed or altered. Notable examples of structures he designed include the Royal College of Physicians (since demolished), Bedlam Hospital (also demolished), and the Monument to the Great Fire of London, co-designed with Christopher Wren. He also designed St. Benet Paul's Wharf Church, which still stands today.

Beyond individual buildings, Hooke was also involved in planning and implementing broader infrastructure projects, such as street layouts and drainage systems. He focused on making London more functional and resilient against future disasters.