Gordon Muchall struck a patient century to put Hampshire firmly on the back foot at the Ageas Bowl.
The Durham all-rounder was finally out on 145 as his side posted a first-innings total of 421 in the County Championship division one clash.
And as the second day was brought to a premature end by rain, Hampshire had reached 119 for three to trail by 302 runs.
The hosts are in desperate need of a victory to boost their hopes of escaping the relegation.
But Muchall’s knock, which spanned 297 balls and included 16 fours, has only cranked up the pressure on Dale Benkenstein’s struggling outfit.
Durham pushed on from their overnight total of 278 for six to take control of the fixture.
Muchall and Usman Arshad helped them ram home their advantage after a tricky first day.
Arshad proved an invaluable partner for Muchall.
The pair added 128 for the seventh wicket before Arshad edged Gareth Berg to James Vince at first slip for 60.
John Hastings then sparked some excitement by smashing a powerful maximum over square leg before swishing a four in the same direction.
Apart from the Arshad wicket, the Hampshire bowling attack struggled in damp but overcast conditions.
Spin eventually finished off the Durham innings.
Hampshire’s teenage leg-spinner Mason Crane bowled Hastings (22) for his maiden first-class wicket.
Liam Dawson then took his 150th when he had Muchall caught by Will Smith.
The left-arm spinner (three for 70) then ended the innings as Graham Onions slogged to Jackson Bird.
Jimmy Adams stepped down from the Hampshire captaincy at the weekend to concentrate on his batting.
But his decision failed to produce a turnaround in form as he departed early in the home side’s reply.
Adams became Chris Rushworth’s 56th Championship wicket of the season when he was trapped leg before wicket for five.
Dawson, who was recalled from his loan stint at Essex for this game, departed for nine before James Vince made a brisk 19.
But it was only Michael Carberry who offered any sustained resistance to the Durham attack as he cruised to 57 not out when the rain arrived.
Smith (27 not out) will resume with him this morning as Hampshire aim to launch a fightback.