An area called "Totoket", which became Branford, was part of the land bought from the Mattabesech Indians in 1638 by the first settlers of New Haven. The Dutch set up a trading post at the mouth of the Branford River in the 1600s, the source of the name "Dutch Wharf."

The town's name is said to be derived from the town of Brentford, England. Established in 1644, the town grew during the 18th and 19th centuries. In the late 18th century, the first shoreline community, Stony Creek, was settled. Indian Neck and Pine Orchard were also settled, but neither of those settlements were permanent until the mid-19th century.

In 1852, the railroad helped bring new business, including Branford Lockworks, Malleable Iron Fittings Company, and the Atlantic Wire Company.

During the mid-nineteenth century, Branford became a popular resort area. Approximately twenty hotels opened, including Indian Point House in Stony Creek, Montowese House in Indian Neck, and Sheldon House in Pine Orchard. During the mid-20th century, Branford shed its resort image and subsequently took on many characteristics typically associated with northeastern suburbs.

In 1974, Connecticut Hospice was founded in Branford, the first hospice in the United States.

Branford Center is home to many small stores, restaurants, and coffee houses, which line Main Street, with the Green at the center. The Branford Green has churches as well as the town hall and other government facilities and hosts concerts and other events, such as the annual Branford Festival.

Branford Hills sits on the western end of town and centers on the heavily commercialized strip of Route 1. Fast-food and sit-down restaurants, auto dealers, grocery stores, and several strip malls are located there.

Branford Hills features many condominum and apartment complexes, most of which house middle and lower-middle-class residents. The original sites of Connecticut Hospice and St. Elizabeth Roman Catholic Church are in Branford Hills.

Indian Neck is in the south-central section of Branford, dominated by a peninsula bordering Branford Harbor. Both Foote Park and John B. Sliney Memorial Park are located within Indian Neck.

Back in the early to mid 20th century Indian Neck was a tourist destination. Trolley service came down to Sybil and Limewood Ave which had its own commercial area. These included Harry's General Store, Bud's Bait Box, The Waverly Inn, Madelyn's Restaurant, Surfside Restaurant, a Candy Store, and Dairy Joy Ice Cream. Much of the area contained second homes, so the beach was an active place. As the area became more year round the commercial business slowly shut-down. In fact the landmark Waverly Inn burned to the ground in the early 70's truly marking the end of an era.

Pine Orchard is situated between Indian Neck and Stony Creek. The Pine Orchard Yacht and Country Club, The Pine Brook School (formerly Wightwood School) a private institution, and Francis Walsh Intermediate School are found here.

Stony Creek is a shorefront section in the southeastern section of Branford, centered on a harbor on Long Island Sound. Stony Creek, an affluent section of Branford along with Pine Orchard, has an ambience of a small seaside village. It is famous for the archipelago of islands knowns as the Thimble Islands.

The Thimbles are a jumble of glacial rocks, ranging from 17 acres (69,000 mē) down to stepping stone size, at the mouth of the harbor. Despite their small size, they possess a wealth of history and local lore, as well as providing pleasant scenery for a summer cruise.

Stony Creek is also home to the all-male Stony Creek Fife & Drum Corps and the all-female Totoket Ancient Fife & Drum Corps. A large quarry is still working, and supplied the distinctive pink/orange Stony Creek granite for the Brooklyn Bridge, the Stony Creek library and the newest House Office Building in Washington, D.C.

Short Beach is a beach neighborhood in the western end of town, south of Branford Hills. It is home to many small islands, the largest being Kelsey Island, which has a few small cabins used as summer homes. Short Beach is home to half of the famous Shoreline Trolley Museum which is also in neighboring East Haven. Also in Short Beach are the Yale Corinthian Yacht Club (YCYC), Short Beach Union Church and three parks, the largest being Pardee Park. Short Beach's population is about 1,500 and features a three-day festival at the end of summer called Short Beach Days. Short Beach is known for the population of monk parakeets that live there (referred to as the "Short Beach Parrots"), a non-native bird.

Hotchkiss Grove is located between Indian Neck and Pine Orchard and consists of 9 Avenues, Hotchkiss Grove Road, and Dudley Road. It has a small beach used for swimming and keeping boats with a raft to swim out to. The point is a small peninsula going out into the water with a small dock and grass, where parties are held sometimes. Every first Saturday of August, Hotchkiss Grove Day is held, with the day starting with a costume parade, with prizes. Then are beach games, in which kids compete with one another on the beach. There is live music at that time and a clam bar. Then there is a dinner on the point in the evening, with a raffle, live auction, and dance.

Branford has six National Register of Historic Places districts, including buildings in Federal, Arts and Crafts, and Queen Anne styles of architecture.

Harrison House and Museum, a 1724 structure, has period furnishings, local historical items, archives, a barn and a herb garden.

Cruises of the Thimble Islands depart from the Stony Creek dock, and seal-watch cruises take place in March.

Branford's recreational facilities include several town-maintained parks and beaches owned by private foundations, hiking trails along Lake Saltonstall and a stretch of the Shoreline Greenway Trail, and 20 miles (30 km) of coastline with more than 12 marinas.