OXFORD United finished with just eight men as they suffered a hugely costly afternoon which did more damage to flagging promotion hopes.
Tom Newey and Michael Raynes were both sent off as United unravelled in the final ten minutes.
Johnny Mullins was also stretchered off and with all three substitutes already used, United had no-one to come on as the game unravelled calamitously.
The game had started almost as badly, with defensive mistakes allowing Ollie Banks and Gary Roberts to open up a two-goal lead in 16 minutes.
United did recover to have their moments going forward, but they could not take advantage and instead Roberts punished the depleted visitors by adding his second in stoppage time.
United's side showed two changes from the one which began the 1-1 draw with Cheltenham Town in midweek.
Danny Rose came into the middle of a five-man midfield, which saw Alfie Potter line up on the left flank. James Constable and David Connolly dropped to the bench.
The visitors had opened the scoring inside a minute on their visit to the Proact Stadium last season and they got away to another good start.
Smalley, playing on his own up front, was fouled out wide and the resulting free-kick was only half-cleared to the edge of the box, where David Hunt unleashed a sweet volley.
Tommy Lee did well to tip the ball over and from the corner Newey stabbed a shot wide.
It was a promising opening, but as with their 2-1 home defeat to Burton Albion a week earlier, the game plan quickly came off the rails.
On eight minutes a fluent move from Chesterfield saw Jay O'Shea cross from the right. Hunt looked well-placed to head clear, but somehow the full back did not make contact. Banks was on hand to profit, controlling the ball and slamming a shot home from eight yards.
It was a poor goal to give away, but it got even worse just after the quarter-hour mark.
Mullins, playing as the anchor man in midfield, was booked for a lunge on Roberts. From the free-kick Smalley inexplicably shoved Ian Evatt, which referee Paul Tierney spotted.
Roberts had no hesitation from 12 yards, converting confidently to give the leaders a two-goal cushion.
For a moment it looked like the hosts might disappear over the horizon, but United were at least able to steady the ship.
Backed by an away end which did not stop chanting until half-time they went in search for a way back into the game.
The visitors were able to keep the ball well for spells, but significantly they rarely stretched the Spireites' defence.
Ryan Williams was their brightest spark, skipping past Ritchie Humphreys a couple of times. On one occasion his cross was met cleanly on the volley by Smalley, but the goal-bound effort was well blocked.
Chesterfield looked the more likely to score and only an excellent block from Newey prevented O'Shea from a clear sight of goal in stoppage time.
The forward curled a free-kick just over early in the second half, before United enjoyed their best spell of the game.
Just before the hour mark Williams seized on a loose ball and burst clear of the defence. He had scored in the previous two games, but Lee did well to block the shot with his legs.
Chesterfield were briefly rattled and after Potter had a shot deflected wide, Lee dropped the resulting corner. The ball fell to Mullins, whose snap shot was straight at the relieved goalkeeper.
With that, hopes of getting back into the game disappeared.
The hosts regained their composure, before United lost theirs.
Newey received a straight red card for coming through the back of Banks and within two minutes Raynes had followed him down the tunnel after collecting a second booking.
Mullins also swiftly departed, this time on a stretcher, and Roberts rounded off a disastrous afternoon by adding a third goal in stoppage time.
Oxford Utd: Clarke, Hunt, Raynes, Wright, Newey, Mullins, Ruffels (Rigg 78), Rose, Williams, Smalley (Constable 70), Potter (Connolly 78).
Unused subs: Crocombe, Whing, Wroe, Bevans.
Chesterfield: Lee, Darikwa, Cooper, Evatt, Humphreys, Ryan, Morsy, O'Shea (Bennett 73), Banks (Kearns 86), Roberts, Richards (Doyle 67).
Unused subs: Dunbavin, Smith, Hird, Gnanduillet.
Referee: Paul Tierney (Lancashire).
Attendance: 6,246 (535 visitors).