Blanche was sailing off Puerto Rico on 19 July 1805 when she was attacked by a French squadron of four ships, led by Captain François-André Baudin in the 40-gun frigate Le Topaze.

Blanche's loss is controversial; while Rear-Admiral John Sutton praised Mudge and his crew for their defence of the outnumbered ship, historians such as William James have criticised the British performance as lacklustre and undistinguished.

The Royal Navy stopped ordering specifically large and offensively capable warships, and instead focused on standardised classes of ships that were usually more moderate in size, but through larger numbers would be able to effectively combat the expected increase in global economic warfare.

[5] The Apollo class was chosen to fulfil the role of standardised frigate because of how well the lone surviving ship of the first batch, HMS Euryalus, had performed, providing "all-round excellence" according to the naval historian Robert Gardiner.

[1][11] After fitting out was completed in January the following year Blanche joined the Baltic Fleet at Yarmouth in preparation to sail to Copenhagen to harass Denmark, part of the Anti-British Second League of Armed Neutrality.

[11] On 19 March Blanche was sent ahead of the fleet to Elsinore, landing the member of parliament Nicholas Vansittart for a meeting with the British Minister to Denmark, William Drummond, so that they could outline the Foreign Secretary Lord Hawkesbury's ultimatum to the Danes.

[13] In preparation to make an attack on Copenhagen, on 27 March Blanche escorted two of the fleet's bomb ships to a position from which they would be able to bombard the fortress of Kronborg.

[1][16] In engaging the Danish line of battle Blanche was part of a flotilla of five frigates under the command of Captain Edward Riou that were to act as a manoeuvrable reserve force.

[14][19][20] Blanche spent the rest of the French Revolutionary Wars attached to Admiral William Cornwallis' Channel Fleet and patrolling the Bay of Biscay.

[19] Captain Barrington Dacres took command of the frigate at the Peace of Amiens in May 1802, serving as part of the Royal Escort to George III at Weymouth for much of the year, and patrolling off Cornwall and Devon combatting smugglers.

[1][14] As the refit was approaching completion Captain Zachary Mudge recommissioned the ship in October, having joined on 23 September, and Blanche left the dockyard in January 1803.

[Note 2][1] Blanche was sailing 100 miles (160 km) north of Puerto Rico at 20°N 66°W / 20°N 66°W / 20; -66 on 19 July 1805, on a journey from Jamaica to Barbados with despatches for Vice-Admiral Lord Nelson, when she was spotted by a French squadron.

The battle began at about 11 a.m. when Topaze reached Blanche, firing at her from her larboard side, while Départment des Landes occupied her starboard quarter, and the other French warships attacked her from astern.

The battle continued for forty-five minutes, with the French destroying all of Blanche's sails and rigging, leaving her unable to manoeuvre and her fore and main masts disabled.

Despite some suggestions that Blanche had not been fully prepared for the fight and had given up too easily, Mudge was honourably acquitted in a court martial at Plymouth on 14 October for losing his ship.

Rear-Admiral John Sutton praised Mudge's "very able and gallant conduct in the defence made by you of his Majesty’s late ship the Blanche, against a very superior force of the enemy’s ships; and likewise of the spirited support afforded you by the officers of every description, as well as the seamen and royal marines, under your command, in the discharge of their duty; and which reflects upon you and them the highest degree of merit and approbation"[21][37] James has questioned how truthful Mudge was in his account of the loss of Blanche, noting how he greatly overestimated the strength of his four opponents in his reports and made suggestions of much higher casualties than had actually occurred.

The French officers involved also negated Mudge's account of an especially hard-fought battle, noting how only Topaze had truly engaged Blanche, with the other vessels firing very few shots at the British ship, and those mostly at the rigging and masts.

James ends his debate on the merits of the defence of Blanche by saying: "We confess our inability to discover any thing calculated to distinguish this case of defence and surrender from others that have occurred; not, at least, on the score of superior merit"[38] The historian E. V. E. Sharpston builds on James' argument, concluding that: "It is difficult to escape the conclusion (reinforced by other episodes in his career) that Mudge was inept, his crew slack, and that neither measured up to Captain Baudin and his crew"[31]Part of Blanche's wreck, including her mainmast, was found floating at 22°N 63°W / 22°N 63°W / 22; -63 by the American schooner Sally on 27 July; the ship then found another mast a mile onward, with rigging and an anchor still attached.

Markings on the recovered material led the captain of Sally to initially announce that he had discovered the destruction of the 74-gun ship of the line HMS Blenheim rather than the remains of Blanche, but this was rectified by a report in The Times on 16 October.