The Knowles-Perry House is typical of the five-bay, two-story houses with gambrel roofs that were built in mid-eighteenth-century Newport. The building has a center chimney and three dormer windows on the third floor that alternate triangular pediments with a curved pediment in the center. This detail, copied from the many English design books illustrating patterns derived from Palladio (and ultimately Vitruvius), was often used during the Georgian period in Newport. Built c.1750, the house stands on the original site. It was purchased by the Newport Restoration Foundation (NRF) in 1970 and restored as a domestic dwelling in 1975-76.

Operation Clapboard negotiated the purchase of the Knowles-Perry House in the mid-1960s and the house then passed to the Preservation Society of Newport County. Some interest had been generated in creating a museum dedicated to Oliver and Matthew Perry, but this interest waned before extensive restoration work had begun and the building was then offered to NRF.

The house appears on the Stiles Map of 1758 and records indicate that Henry Knowles was most likely the first owner. He deeded a house and lot (#147 of the Quaker Lands) to Thomas Rodman in 1761. The records of ownership next state that Christopher Perry of South Kingstown was given the house and land in 1800 by his father-in-law. It is not known when the Perry family began living in the house. Some think it was just before 1800, others say it may have been closer to 1794, the year Matthew Calbraith Perry was born.

There are conflicting reports on the Perry brothers. Oliver Hazard Perry's place of birth is certain, while his date of birth is unclear. He was born in South Kingstown on either August 20 or 23, 1785. Conversely, Matthew Calbraith Perry's date of birth on April 10, 1794 is certain, but his actual place of birth remains in question. He was born either in South Kingstown or in Newport. It is reported in more than one source that Matthew spent his boyhood in the house on Walnut Street, as did Oliver. He, however, was nine years older than Matthew and probably spent less time in the house.

Both Perry brothers went on to have distinguished naval careers, Oliver Hazard at the Battle of Lake Erie in 1818, and Matthew Calbraith in opening the ports of Japan beginning in 1853. As a result of those exploits, their likenesses can still be viewed in Newport. A statue of Oliver Hazard Perry stands in Washington Square across from his house at 29 Touro Street, while a statue of Matthew Calbraith Perry surveys the Newport Art Museum from Tour Park on Bellevue Avenue.

The Knowles-Perry House underwent significant alterations throughout the late nineteenth and early twentieth centuries. The house was converted into a corner neighborhood market at the Second and Walnut Street intersection, and a second storefront was added later to the east of the front entry on Walnut Street. The original doorway was given Victorian embellishments and provided access to several apartments on the top two floors.

Converting the ground floor of eighteenth-century buildings into commercial store space was not uncommon in Newport during the late nineteenth and early twentieth centuries. However, the process was invasive as illustrated by the results at the Knowles-Perry House. Nearly the entire first floor was removed and the basement filled in to create a street-level floor to ease access. When the second store was added, a few steel I-beams were used to support the second and third floors. The chimney(s) was also removed. Whether or not the original house had a center chimney or instead had two interior chimneys is uncertain. Either arrangement could have been used in a house of this size and period.

During the restoration, a new center chimney with seven fireplaces was built, modeled on existing and similar eighteenth-century examples. The stairway, paneled room-ends, wainscoting, doors, and other interior details were taken from the NRF inventory of period materials or reproduced from old patterns.