About 1703 he took up residence in Philadelphia, where he became a merchant, and stood among the most influential of the Quakers of his day.

During the same year James Logan, desiring William Penn, founder and proprietor of Pennsylvania, to consider whom to add to the property commission, wrote to him, saying: "Samuel Preston is also a very good man, and now makes a figure, and, indeed, Rachel's husband ought particularly to be taken notice of, for it has too long been neglected, even for thy own interest."

Almost immediately afterward, Preston was called to the council, on which he served until he died.

He was chosen mayor of Philadelphia in 1711, and in 1714 became the treasurer of the province, retaining the office until his death.

In 1726 he became a justice of the peace and of the court of common pleas, and in 1728 one of the commissioners of property, which office he held many years.