NSW were bowled out for just 203 on a challenging Lavington Sports Ground surface on Thursday.
At stumps, Victoria had reached 1-15 with Marcus Harris and nighwatchman Mitch Perry both unbeaten on seven.
NSW fast bowler Trent Copeland, playing his first Shield match for nearly 12 months, dismissed Travis Dean for one.
Second-placed Victoria are jousting with Queensland for a spot in the Shield final with one further round to be played.
Prolific opener Hughes has been a stand-out for NSW in a disappointing season, but he limped off with a calf injury and retired hurt on 22.
He went for late afternoon scans and his participation in the remainder of the match, and next week's last match against South Australia, is in serious doubt.
Hughes has easily been NSW's best performer this summer being the side's leading Shield run-getter, as well as hitting a record-equalling four one-day centuries.
NSW's day could barely have begun in worse fashion with young opener Blake Nikitaras caught behind without scoring off Perry from the third ball of the day.
It was the first of a four-wicket return for the consistent Perry, following on from an eight-wicket haul last week, the 22-year-old ending with 4-24 from 14.3 overs.
Fellow opening bowler Fergus O'Neill picked up 2-50 on a day when all bar one of the wickets to fall was caught in the slips or by wicketkeeper Sam Harper.
NSW slipped to 3-43 before lunch, and then 6-119 with all the recognised batters back in the pavilion.
But Chris Green continued his recent lower-order form with the bat, hitting 52 at No.8 to help lift NSW past 200.
Moises Henriques was next best with 29, while Ollie Davies made a promising 28 on debut.
Both sides lined up without rested personnel ahead of the upcoming one-day International series in India; Sean Abbott for NSW and Glenn Maxwell for Victoria.
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