Fitzgerald left Superior, Wisconsin on the afternoon of November 9, 1975 under Captain Ernest M. McSorley. She was en route to the steel mill on Zug Island, near Detroit, Michigan, with a full cargo of taconite. A second freighter, Arthur M. Anderson, destined for Gary, Indiana out of Two Harbors, Minnesota, joined up with Fitzgerald. Fitzgerald, being the faster ship, took the lead while Anderson trailed not far behind.

Crossing Lake Superior at about 13 knots (15 mph, 24 km/h), the boats encountered a massive winter storm, reporting winds in excess of 50 knots (90 km/h) and waves as high as 35 feet (10 m). Because of the storm, the Soo Locks were closed. The freighters altered their courses northward, seeking shelter along the Canadian coast. Later, they would cross to Whitefish Bay and approach the Sault Ste. Marie locks.

On the afternoon of November 10, Fitzgerald reported a minor list developing and top-side damage including the loss of radar, but did not indicate a serious problem. She slowed to come within range of receiving Anderson's radar data and for a time Anderson guided the Fitzgerald toward the relative safety of Whitefish Bay. The last communication from the boat came at approximately 19:10 (7:10 PM), when Anderson notified Fitzgerald of being hit by rogue waves or perhaps seiche waves large enough to be caught on radar, that were heading Fitzgerald's way and asked how she was doing. McSorley reported, "We are holding our own." A few minutes later, she suddenly sank – no distress signal was received. A short ten minutes later Anderson could neither raise Fitzgerald nor detect her on radar. At 20:32, Anderson informed the U.S. Coast Guard of their concern for the boat.

Once Anderson noted the loss of Fitzgerald, a search was launched for survivors. The initial search consisted of Anderson, and a second freighter, SS William Clay Ford. The efforts of a third freighter, the Canadian vessel Hilda Marjanne, were foiled by the weather. The U.S. Coast Guard launched three aircraft, but could not mobilize any ships. A Coast Guard buoy tender, Woodrush, was able to launch within two and a half hours, but took a day to arrive. The search recovered debris, including lifeboats and rafts, but no survivors.