Nick Hewat, commercial director at Guardian News & Media, and Natasha Murray, director of client partnerships at the newspaper, are leaving the business.
Hewat ends a seven-year stint at the Guardian during which time he has been in charge of the sales teams and the newspaper's commercial direction.
The Guardian won Sales Team of the Year at Campaign's Media Week Awards twice during the period, in 2014 and 2018.
Before joining the company in 2013, Hewat was group sales director at Telegraph Media Group for four years. He has also worked at Absolute Radio and Capital Radio.
Murray has been at the Guardian for more than three years, having joined from Havas Media.
Murray and Hewat are set to depart at the end of the year.
The changes are part of a restructure of the business under which Adam Foley takes on the new position of director of advertising, UK, as Campaign reported this week.
Like other businesses, GNM has had a tough time throughout the coronavirus pandemic. In April, Campaign reported that it furloughed about 100 UK staff and temporarily cut its management team's pay as it faced "huge financial challenges" caused by the pandemic.
A spokesperson for GNM said: "We can confirm that Natasha Murray and Nick Hewat have chosen to leave The Guardian. We would like to thank them for all their hard work and wish them the best in their future endeavours."