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Throughout the 17th century Plymouth had gradually lost its pre-eminence as a trading port. By the mid-1600s commodities manufactured elsewhere in England cost too much to transport to Plymouth and the city had no means of processing sugar or tobacco imports, although it played a relatively small part in the Atlantic slave trade during the early 1700s. In 1690 the first dockyard, HMNB Devonport, opened on the banks of the Tamar and further docks were built in 1727, 1762 and 1793. In the 18th century new houses were built near the dock, called Plymouth Dock at the time, and a new town grew up. In 1712 there were 318 men employed and by 1733 it had grown to a population of 3,000 people.

Prior to the latter half of the 18th century grain, timber and then coal were the greatest imports. During this time the real source of wealth and the major employer in the region became the dockyard. The Three Towns conurbation of Plymouth, Stonehouse and Devonport enjoyed some prosperity during the late 18th and early 19th century and were enriched by a series of neo-classical urban developments designed by London architect John Foulston. Foulston was important for the town and was responsible for several grand public buildings, many now destroyed, including the Athenaeum, the Theatre Royal and Royal Hotel, and much of Union Street.

The mile-long Breakwater in Plymouth Sound was designed by John Rennie and work started in 1812; numerous technical difficulties and repeated storm damage meant that it was not completed until 1841, twenty years after Rennie's death. In the 1860s, a ring of Palmerston forts was constructed around the outskirts of Plymouth, to protect it from attack from any direction. Some of the greatest imports to Plymouth from the Americas and Europe during the latter half of the 19th century included maize, wheat, barley, sugar cane, guano, sodium nitrate and phosphate. Aside from the dockyard, other industries such as the gasworks, the railways and tramways and a number of small chemical works had begun to develop in the 19th century continuing into the 20th century.

During World War I, Plymouth was the port of entry for many troops from around the Empire and also developed as a facility for the manufacture of munitions. Although major units of the Royal Navy moved to the safety of Scapa Flow, Devonport was an important base for escort vessels and repairs. Flying boats operated from Mount Batten.

In World War II, Devonport was the headquarters of Western Approaches Command until 1941 and Sunderland flying boats were operated by the Royal Australian Air Force. It was an important embarkation point for US troops for D-Day. The city was heavily bombed by the Luftwaffe, in a series of 59 raids known as the Plymouth Blitz. Although the dockyards were the principal targets, much of the city centre and over 3,700 houses were completely destroyed and more than 1,000 civilians lost their lives. This was largely due to Plymouth's status as a major port Charles Church was hit by incendiary bombs and partially destroyed in 1941 during the Blitz, but has not been demolished, as it is now an official permanent monument to the bombing of Plymouth during World War II.

The redevelopment of the city was planned by Sir Patrick Abercrombie in 1943 and by 1964 over 20,000 new homes had been built. Most of the shops had been destroyed and those that remained were cleared to enable a zoned reconstruction according to his plan.

Postwar, Devonport Dockyard was kept busy refitting aircraft carriers such as the Ark Royal. By the time this work ended in the late 1970s the nuclear submarine base was operational. The army had substantially left the city by 1971, with barracks pulled down in the 1960s, however the city has become home to the 42 Commando of the Royal Marines.