Eleven ships, including six transports, carried 772 convicts, officers, marines, crews, and some wives and children, travelled more than 10,000 miles (16,000 km) to reach the unknown shore.
On arrival at Port Jackson, Sydney Harbour, the surgeons had the difficult task of attending to the sick in tents while supervising the construction of emergency timber hospital huts.
Ralph Clark commented "it would not have rested there had the governor not taken the matter in hand and convinced the two sons of Aescalipius that it was much better to draw blood with the point of their lance from the arm of their patients than to do it with pistol balls from each other.
When White was absent from the settlement, Balmain found himself in charge of the makeshift hospital, stocked with only rudimentary supplies, and assisted by untrained convict personnel.
The treatment of the convicts had been so harsh that they were confronted with large numbers of sick and dying people, and the death rate rose alarmingly over a two-month period.
Henry Waterhouse described the operation: "We got up within two hours to Sydney Cove, when the surgeons were immediately sent for and Mr Balmain attended with his instruments.
How well Balmain had known her in Sydney is not known, but they formed a de facto relationship that resulted in the birth of a daughter named Ann, on Norfolk Island in May 1794.
In this role he signed a proclamation fixing the prices for labour and goods, and declaring that monies gained by duties levied on the sale of spirits were to be spent on the establishment of schools.
By this time there were 1600 settlers and several thousand convicts, but Balmain had only one assistant surgeon and found the task of caring for the health of the entire population arduous and frustrating.
He petitioned the new Governor, John Hunter for assistance and an increase in salary but was rewarded only by appointment as Civil Magistrate in New South Wales.
In his role as magistrate he had the challenging task of maintaining an uneasy peace between the often arrogant soldiers of the New South Wales Corps and the settlers, both free and emancipist (ex-convicts).
Among other civic duties, Balmain was a member of the Orphan House Committee in September 1800, set up to supervise orphanages in Sydney and Parramatta.
He was one of a number of prominent citizens, including his former adversary John Macarthur, who formed a consortium to privately charter a ship for trade with India.
Governor Hunter permitted the vessel to land, although the British government had issued clear instructions to stop the trading the military.
He soon met with Sir Joseph Banks, describing the growth of New South Wales, and submitting a paper presenting his views on the customs and laws of the colony.
Balmain had left D'Arcy Wentworth, whom he had first met on Norfolk Island, in charge of his affairs in the colony, including selling his remaining rum stocks, taking over his private agency, and acting as attorney on his investments.
In December 1802 his leave was terminated and he was instructed to return to Sydney, but objected on the grounds of unsettled private affairs and family engagements.
His old foe and trading partner John Macarthur attended the funeral, as did Henry Ball, commander of the First Fleet vessel HMS Supply.
In his will Balmain provided a yearly sum of £50 for "my dear friend Margaret Dawson, otherwise Henderson … whose tenderness to me, while in ill health, claims my warmest gratitude".