He succeeded his father in 1745 and to the baronetcy and the estates, including Lowther Castle, of his great-uncle Henry Lowther, 3rd Viscount Lonsdale on 6 March 1751. He also inherited the estates of Sir William Lowther, 3rd Baronet of Marske on 15 April 1756 and the estates of his cousin Sir James Lowther, 4th Baronet of Whitehaven in 1755.
Lowther exercised influence over a number of "rotten" or "pocket" boroughs, including Appleby, a classic example of this type of constituency. In 1761 he was credited with securing the return of eight MPs — two each for Cumberland, Westmorland, and Cockermouth, and one each for Appleby and Carlisle.
He married Mary Crichton-Stuart, daughter of John Stuart, 3rd Earl of Bute and Mary Wortley-Montagu, 1st Baroness Mount Stuart on 7 September 1761 and had a string of mistresses. He fell in love with the daughter of one of his tenants and made her his mistress keeping her in luxury. When she died he could not endure to have her buried and the body remained lying in bed until the increasing putrefaction became unbearable. He then had her body placed in a glass topped coffin that was placed in a cupboard. Eventually her body was buried in Paddington cemetery.
He was created Earl of Lonsdale on 24 May 1784 and Viscount Lowther on 26 October 1797, with special remainder to his third cousin Sir William Lowther, 2nd Baronet of Little Preston.