Matt Critchley took 3-133 on a tough day for the Derbyshire bowlers as Sussex piled on the runs to set the visitors a record chase at The 1st Central County Ground.
Derbyshire were only able to add 74 runs to their overnight score, eventually all out for 389 in their first innings as Billy Godleman top-scored with 122.
The Sussex top order quickly built a commanding lead, before declaring on 353-6 to set Derbyshire 405 runs to win in another high-scoring day on the South Coast.
Resuming on 315-5, Critchley (8) joined Alex Hughes (77) at the crease, but both were soon out to Ollie Robinson (3-77) as he struck twice in as many overs.
Daryn Smit (20 not out) and Tony Palladino (9) added 41 valuable runs for the eighth wicket, but the final two wickets fell with the score on 389.
With Ravi Rampaul unable to play any further part in the match and due to be reviewed by a specialist later this week in Derby, the ninth wicket marked the end of the Derbyshire innings.
Carrying a 51-run first innings lead, Sussex survived until lunch and then came out aggressively in the second session, attacking all Derbyshire bowlers with a view to building a quick and insurmountable lead.
Openers Phil Salt and Luke Wells added 191 for the first wicket in just under 32 overs before Critchley got the breakthrough to remove Wells for 78.
However, Salt powered on and the lead soon went past 250 and the opener hit boundaries around the ground to surpass his previous first-class best.
Tom Haines was out to Critchley for 27 and Palladino eventually removed Salt for a well-made 148, but the hosts remained in control with the lead 321.
Hardus Viljoen had Michael Burgess (4) lbw and Critchley removed David Wiese (12) to pick up his third, but the Sussex lead continued to grow until Ben Brown declared on 353-6.
With seven overs to negotiate at the end of the day, Ben Slater (yet to score) and Godleman (1 not out) defended well and safely guided Derbyshire to 6-0 at the close, needing a further 399 runs to win on the final day.
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