Gaine came from a working-class family in Ireland, and entered into a five-year apprenticeship with James Macgee in Belfast before emigrating at the age of eighteen to New York City in 1745.

He became a journeyman and worked for six years under James Parker, who was the official printer for the city of New York, before becoming proficient enough and publishing his own newspaper.

[1][2] Gaine purchased a modest property in Hanover square, and used his house as book and stationery store, while he increased his printing, where his business ventures soon became extensive and successful.

[7] When the British moved on New York City early in the American Revolutionary War, he crossed the river to Newark, New Jersey, and published a lukewarm pro-independence newspaper.

[7][9] When the Revolutionary war ended Gaine submitted a petition to remain in New York City, which was granted, but soon after he was compelled to hand over the publication of his failed newspaper, and confine his business ventures to private printing and bookselling, which he did do well at.

[4] Gaine started out in life as a poor man, but was said to be punctual in his business dealings, and "of correct moral habits, and respectable as a citizen", and became the founder of two New York newspapers.