Rothermere married Claudia Caroline Clemence, daughter of Terence J. Clemence, on 15 July 1993. They have five children:

Harmsworth held various positions in Associated Newspapers and was managing Director of the Evening Standard, when the sudden death of his Father in 1998 resulted in his becoming the controlling shareholder and chairman of Associated and of its parent Daily Mail and General Trust just before his 31st birthday. One change he has instituted since becoming chairman is requiring Directors to retire at age 75.

In 2002, The Guardian reported that Rothermere had fathered another son from a relationship prior to his marriage. Rothermere confirmed this in his testimony to the Leveson Inquiry.

He ranked fourth in the Publishing, Advertising, and PR section of the Sunday Times Rich List 2013 with an estimated wealth of £720 million. In April 2015, the Sunday Times estimated his net worth at £1 billion He has non-domicile tax status and owns his media businesses through a complex structure of offshore holdings and trusts.

The BBC's Newsnight programme at the end of January 2017 reported that former prime minister David Cameron had approached Lord Rothermere to sack Eurosceptic Paul Dacre, the Editor of the Daily Mail in the run up to the 2016 EU membership referendum. A representative of Lord Rothermere refused to confirm or deny the story, although a spokesman for Cameron confirmed that had tried to persuade both Dacre and Rothermere over the vote. Rothermere's representative told the media: "Over the years, Lord Rothermere has been leant on by more than one prime minister to remove Associated Newspapers’ editors but, as he told Lord Justice Leveson on oath, he does not interfere with the editorial policies of his papers".