On 3 December 1674, he married Lady Katherine Thynne (d. bef. 1713), daughter of Sir Henry Frederick Thynne, 1st Baronet. They had children:

• Richard Lowther, 2nd Viscount Lonsdale (d. 1713)
• Henry Lowther, 3rd Viscount Lonsdale (d. 1751)
• Hon. Mary Lowther (c.1676 – 16 April 1706), married in February 1692 Sir John Wentworth, 1st Baronet
• Hon. Elizabeth Lowther, married on 6 August 1695 Sir William Ramsden, 2nd Baronet
• Hon. Margaret Lowther (d. 15 September 1728), married on 20 April 1706 Sir Joseph Pennington, 2nd Baronet
• Hon. Barbara Lowther (d. 1716), married c.1703 Thomas Howard of Corby (d. 1740)
• Hon. Anthony Lowther (d. 1741)
• Hon. Jane Lowther (d. 1752), unmarried

Before this creation John had succeeded his grandfather, another Sir John Lowther (d. 1675), as a baronet, and was twice member of parliament for Westmorland between 1677 and 1696. In 1688 he was serviceable in securing Cumberland and Westmorland for King William III, and was appointed to the Privy Council in 1689. In 1690 he was first lord of the treasury, and he was Lord Privy Seal from March 1699 until his death. On 20 December 1699, he was admitted a Fellow of the Royal Society.

Lonsdale wrote Memoirs of the Reign of James II, which were printed in 1808 and again in 1857. His family became extinct when his son Henry, the 3rd viscount (1694–1751), died unmarried in March 1751.

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