The 16th and 17th Centuries saw the City of London grow with the expansion of world trade. The wharves of the Pool of London were thick with sea-going vessels while naval dockyards were built at Deptford. The Dutch navy even entered the Thames in 1667 in the raid on the Medway.

A cold series of winters led to the Thames freezing over above London Bridge, and this led to the first Frost Fair in 1607, complete with a tent city set up on the river itself and offering a number of amusements, including ice bowling. In good conditions barges travelled daily from Oxford to London carrying timber and wool, foodstuffs and livestock, battling with the millers on the way. The stone from the Cotswolds used to rebuild St Paul’s Cathedral after the Great Fire in 1666 was brought all the way down from Radcot. The Thames provided the major highway between London and Westminster in the 16th and 17th centuries and the clannish guild of watermen ferried Londoners from landing to landing and tolerated no outside interference. In AD 1715 Thomas Doggett was so grateful to a local waterman for his efforts to ferry him home pulling against the tide, that he set up a rowing race for professional watermen known as “Doggett's Coat and Badge”.

By the 18th century, the Thames was one of the world's busiest waterways, as London became the centre of the vast, mercantile British Empire and progressively over the next century the docks expanded in the Isle of Dogs and beyond.. Efforts were made to resolve the navigation conflicts up stream by building locks along the Thames. After temperatures began to rise again, starting in 1814, the river stopped freezing over completely. The building of a new London Bridge in 1825 with fewer pillars than the old, allowed the river to flow more freely and reduced the likelihood of freezing over in cold winters.

The Victorian era was an era of imaginative engineering. In the 'Great Stink' of 1858, pollution in the river reached such proportions that sittings at the House of Commons at Westminster had to be abandoned. A concerted effort to contain the city's sewage, by constructing massive sewers on the north and south river embankments followed, under the supervision of engineer Joseph Bazalgette. Meanwhile, similar huge undertakings took place to ensure water supply, with the building of reservoirs and pumping stations on the river to the west of London. The embankments in London house the water supply to homes, plus the sewers, and protect London from flood. The coming of rail added both spectacular and ugly railway bridges to fine range of earlier road bridges but reduced commercial activity on the river. However sporting and leisure use increased with the establishment of regattas like Henley and The Boat Race. On 3 September 1878, one of the worst river disasters in England took place, when the crowded pleasure boat Princess Alice collided with the Bywell Castle, killing over 640 people.