The Saco Museum's collection contains more than 10,000 artifacts, including superb collections of documented local furniture, clocks, and other decorative arts such as silver, ceramics, textiles and costumes. The museum is well known for its rich collection of paintings and portraits from the Saco River region, and the finest and largest collection of portraits by the renowned deaf artist John Brewster, Jr. (1766 - 1854). Other regional artists represented in the collection include Gibeon Elden Bradbury (1833 - 1904) and Charles Henry Granger (1812 - 1893). Charles Henry Granger was one of the founding members of the Institute. The sculpture collection includes works by Charles Granger, Katherine Tupper Prescott, and John Rogers.

Besides the fine arts, the museum houses a number of rare treasures of national significance. The Scamman Jug is a remarkably preserved Westerwald jug bearing a medallion of King William III, which was first owned by Humphrey Scamman (1640 - 1727) of Saco. The Walcott/Johnson camera was the first daguerreotype portrait camera in the United States, built in 1840 and presented to the Institute by its first president, John Johnson. Another rare artifact is the 850-foot long Panorama of Pilgrim's Progress. One of only a handful of 19th century panoramas to survive, the Pilgrim's Progress was painted in New York in 1851 by a group of artists and illustrators associated with the National Academy of Design. It is a unique and unforgettable example of this nearly extinct art form.