Charles II of England, the first cousin of Louis XIV, proposed to Hortense in 1659, but his offer was rejected by Cardinal Mazarin who believed the exiled king to have little in the way of prospects. Mazarin realised his mistake when Charles was reinstated as King of England only months later. Mazarin then became the supplicant and offered a dowry of 5 million livres, but Charles refused. While a marriage did not materialise, the two were to cross paths later.
Leaving her small children behind, Hortense finally made a bid to escape from her hellish marriage on the night of 13 June 1668, with help from her brother, Philippe. The French king Louis XIV declared himself her protector and granted an annual pension of 24 thousand livres. Her former suitor, Charles Emmanuel II, Duke of Savoy, also declared himself her protector. After the death of Savoy, Hortense had no source of income; her husband froze all of her income, including the pension from Louis XIV.
The English ambassador to France, Ralph Montagu, aware of Hortense's desperate situation, enlisted her help in increasing his own standing with Charles II. He hoped she would replace the king's current mistress, Louise de Kerouaille, Duchess of Portsmouth. Hortense was willing to try. In 1675, she travelled to London under the pretext of a visit to her young niece, Mary of Modena, the new wife of Charles II's younger brother, James, Duke of York. She was dressed as a man.
By mid-1676, Hortense had fulfilled her purpose; she had taken the place of Louise de Kerouaille in Charles's affections. He provided her a pension of £4,000, which considerably lightened her financial troubles.
Montagu recounted: "I went to see Madame de Portsmouth [Louise de Kerouaille]. She opened her heart to me... explained to me what grief the frequent visits of the King of England to Madame de Sussex [Hortense Mancini] cause her every day."
Such state of affairs might have continued had it not been for Hortense's promiscuity. She was dubbed as the 'Italian Whore' in England.
Firstly, there was her almost certainly sexual relationship with Anne, Countess of Sussex, the king's illegitimate daughter by the Duchess of Cleveland. This culminated in a very public, friendly fencing match in St. James's Park, with the women clad in nightgowns, after which Anne's husband ordered his wife to the country. There she refused to do anything but lie in bed, repeatedly kissing a miniature of Hortense.
Secondly, she began an affair with Louis I de Grimaldi, Prince de Monaco. Charles remonstrated with her and cut off her pension, although within a couple of days he repented and restarted the payments. However, this signified the end of Hortense's position as the king's favourite. Though she and Charles remained friends, the Duchess of Portsmouth returned to her role as ’maitresse en titre’.
Hortense, however, maintained good relations with the king until his death.