Her first war years were unusually profitable. In 1793 Rear-Admiral John Gell hoisted his flag in her and, commanding the Mediterranean division, took the Spanish-registered prize St Jago, whose cargo was valued at £935,000 — on the order of a hundred million pounds today. St George carried it home to Portsmouth. That October Gell forced the surrender of the French frigate Modeste at Genoa; ill health then took him home for the last time. She was at the Battle of the Hyères Islands in 1795, and in 1798 several of her crew were court-martialled for mutiny — this navy held together on discipline as much as on loyalty. At Copenhagen in 1801 she carried Nelson's flag until he shifted to the shallower-draught Elephant for the attack. Her captain was Thomas Masterman Hardy, who would hold Nelson as he died at Trafalgar.

After the British bombardment of Copenhagen in 1807 and the seizure of the Danish fleet, Britain and Denmark-Norway fought the Gunboat War, and every British merchantman in the Baltic needed escorting past privateers. On 1 November 1811 the last homeward convoy of the season — 129 merchant ships — sailed from Hanöbukten at Karlshamn under Vice-Admiral James Saumarez in Victory, with Rear-Admiral Robert Carthew Reynolds flying his flag in St George. A storm turned them straight back. They sailed again on 9 November and were driven to anchor at Rødsand, a shoal south of Lolland, where twelve merchant ships were lost outright. On 15 November she collided with another vessel and went aground, losing every mast and her rudder. Thirty hours later she was floated off, jury-rigged, and fitted with a temporary Pakenham rudder built from Cressy's timber. Cressy towed her out on 21 November.

The convoy reached Vinga, off Gothenburg, on 1 December; St George limped in the next day for further repairs. Saumarez had grave misgivings about a crippled second rate attempting the North Sea in midwinter. Reynolds and Captain Daniel Oliver Guion insisted she could make the crossing. She sailed on 16 December with around 150 merchantmen and eight ships of the line, Defence and Cressy assigned to shepherd her and the damaged Hero. On the 19th the Skagerrak beat them back, and Cressy took her in tow — the makeshift rudder, held by chain and rope, could not hold a course. They sheltered off the Sälö light on the 21st, then went again. On the 23rd an extratropical cyclone came out of the northwest. Cressy and the brig Bellette clawed away from the coast and lived. Defence tried to take St George in tow, the hawser broke, and Defence went ashore with all but a handful of her 597 men — her own story, a few miles up the same beach.

Before dawn on 24 December they tried to turn her downwind. The jib blew out. The topsail would not set, and tarpaulins spread in the netting gave no steerage. The anchor went down, the cable fouled the temporary rudder and broke it, and after that St George went where the sea sent her. At six in the morning she struck the outermost bar, 500 metres from shore and a few kilometres south of Thorsminde. She listed at once with ten feet of water below; masts were cut away to ease her, every hand went to the pumps, and all the boats but the longboat went over the side. Fourteen men got the longboat away and it capsized; all drowned. The axes had gone with the boats, so the mizzen was cut through with knives. At ten o'clock a surge took some four hundred men into the water, many already dead of cold and exhaustion before it reached them. By noon she was no longer under command. Around a hundred and fifty were still aboard at dusk.

On Christmas Day about ten men reached a raft; four survived the landing, and eight more came in clinging to drifting timber. By the 26th there was no movement on the wreck. Of roughly 738 aboard, the interrogation records suggest twelve lived; some sources say as few as seven. Reynolds's body was never found, nor Guion's. Nearly 1,400 dead from St George and Defence washed up along this coast over the next fortnight, and the Danes — at war with Britain, receiving the enemy's drowned — buried them in the Thorsminde dunes, since called Dead Men's Dunes. The survivors were treated well and exchanged for twice their number of Danish prisoners. One, William Watson, was an American pressed into the Royal Navy who said plainly he wanted neither England nor the service again. A monument went up on the dunes in 1937. A storm in 1981 tore the wreck open again, and the thousands of objects lifted from her since fill the Strandingsmuseum St George at Thorsminde, a few hundred metres from the graves.