Antoine LeCounte, a guide and explorer, was the first settler to this area. He arrived in 1848, but did not settle until 1852. He carried mail from the Red River country to points south, trading goods to Native Americans for horses on the way. LeCounte built the first cabin at what is now East Medicine Lake Blvd. at 29th Ave. N. Plymouth's beginning as a town occurred in 1855 on the northwest shores of what is now known as Parkers Lake. A gristmill and other structures were built in the area. In the spring of 1857, when Parkers Lake flooded, the mill was taken down and moved to Freeport, Minnesota. Freeport is now called Wayzata.

As new settlers came to the area, they decided to organize. The Hennepin County Board of Commissioners named the new settlement Plymouth. On April 19, 1858, a group of townspeople met at the home of Francis Day to open elections for town offices. On May 11, 1858, the group voted to change the town's name to Medicine Lake. This was used once at the town meeting, but for reasons, which were not recorded, it was never used again.

In 1862, during the conflict between white settlers and the Dakota at Fort Ridgeley, near New Ulm, the settlers of Plymouth formed a militia. When the Civil War started, Plymouth paid its volunteers $25 to enlist. At about this time, Plymouth's growth began to take on a new look. Schools and churches were built and a post office was located in Plymouth. By 1863, hotels were being built.