The Samuel R. Knox Papers contain correspondence, orders, and business records from Knox's service in the United States Navy, along with personal letters and papers.

Series I. Early Naval Career and Surveying Expeditions includes papers from his voyages during this time aboard the U.S. frigate Guerriere (1828-1833), such as personal and naval correspondence and lists of officers. Letters regarding his furlough from the Navy and paid expedition for H. Boardman are included in this series (1835-1836). Documentation of his discharge from and reinstatement into the Navy (1836-1837) is contained in this series, as well as orders to Knox aboard the U.S. schooner Hadassah from Commander Charles Wilkes during the Georges Shoals Expedition (1837).

Series II. U.S. Exploring Expedition includes correspondence during the United States Exploring Expedition (1838-1842) including orders and remonstrations from Commander Charles Wilkes on the brigantine Dolphin, the tender Flying Fish, and U.S. ship Vincennes. Letters to brother Robert Knox, Jr. (1802-circa 1880) include descriptions of many elements of the trip, including the landscapes, weather, wildlife, and indigenous groups Knox encountered.

Series III. Mid-period Naval Services contains miscellaneous orders and lists regarding the U.S. ship Albany and nearby naval vessels and published documents regarding tariffs and trade during the Mexican-American War. Documentation of the U.S. Navy activities and officer opinions of the war can be found in letters (1846-1848) to his father Robert Knox, Sr. (1770-1857) and brother, Robert Knox, Jr. This series also includes orders from Commander Pinkney for the U.S. schooner Flirt (1847) as well as receipts and lists relating to Knox's time on the U.S. ship Cumberland and U.S. schooner Wasp (1848) and postwar correspondence with the U.S. Treasury Department regarding payment (1852-1853).

Series IV. Late Naval Career includes orders, bills, and lists from the U.S. ship Massachusetts (1849-1852) and his detachment from the U.S. receiving ship Ohio (1853). Letters to Robert Knox, Jr. contain family information and document voyages. Papers during his time as a Light House Inspector for the 2nd District in Boston (1853-1855) are mostly made up of bills and receipts for repairs. Of particular interest is correspondence with Hon. Daniel W. Gooch regarding payment for retired naval officers, reflective of promotions, including a potential lawsuit (1856-1867).

Series V. Personal Correspondence and Papers includes personal letters from sisters Helena Augusta Bainbridge Knox (1815-1880) and Elizabeth Barrett Knox (1807-circa 1880), as well as various acquaintances. Also included are mortgage and loan documents, architectural plans, and personal bills and receipts.