Webber seized his chance after being recalled to the Blades starting line-up with fine strikes in each half, while on-loan Portsmouth striker Vincent Pericard scored on his full debut and substitute Alan Quinn curled home a 25-yard free-kick.
Both Webber and Pericard justified Blades boss Neil Warnock's decision to rest strike pair Steve Kabba and Neil Shipperley as United chalked up their 12th win from 14 matches to go five points clear of nearest rivals Reading.
Millwall went into the game unbeaten in seven matches and started brightly in a frenetic opening, but a two-goal burst in three first-half minutes sucked the wind from their sails and there was never any doubt as to the outcome.
Neither side created a clear-cut chance in a frantic opening quarter, with the early talking point being Philip Ifil's deserved booking for his foul on Michael Tonge, back in the Blades starting line-up in place of Quinn.
Matt Lawrence returned in place of Paul Robinson for Millwall, but former Sheffield United duo Carl Asaba and Barry Hayles missed out for the Lions through injury and suspension respectively, meaning a return up front for Ben May.
Blades boss Warnock was forced into his first change of the evening when Rob Kozluk sustained injury, with Derek Geary stepping off the bench.
United winger Paul Ifill, an £800,000 summer signing from Millwall, had first sight of goal with a right-foot shot from 20 yards that flew wide.
But the Blades deservedly edged ahead in the 33rd minute thanks to a stunning strike from Webber, who turned sharply 25 yards out and unleashed an unstoppable shot into top right-hand corner.
Warnock's side doubled their advantage three minutes later. Unsworth's corner was flicked on by Chris Morgan and Pericard nodded home the simplest of chances at the far post.
Blades' substitute Quinn replaced Unsworth at the interval, while Millwall boss Colin Lee sent on Carlos Fangueiro for Josh Simpson shortly after.
It made little difference to the pattern of play however, the visitors resuming in control and Webber threatening with a long-range strike, while Millwall created nothing in the final third.
It came as no surprise when the Blades increased their lead in the 68th minute. Pericard used his strength to earn a foul following Ifil's challenge on the edge of the penalty area and substitute Quinn curled a fine 25-yard free-kick into the top corner.
Webber then cut inside Ifil on the left into the penalty area after being sent clear by Geary and clipped an inch-perfect right-foot shot around Millwall goalkeeper Andy Marshall to make it 4-0 five minutes later.
Jody Morris was replaced by Marvin Elliott in the Millwall midfield and Blades winger Ifill was replaced by Keith Gillespie, but the contest was over the moment Quinn's free-kick flew in.