Defence was at a premium on an eventful night that saw Brentford beat Dagenham and Redbridge 4-2 on penalties after a staggering 12 goals were shared at 6-6 after extra time.
But cup specialists of Wigan, who won the FA Cup in 2013 before reaching the semi-finals in 2014, were the biggest side to exit the competition at the first stage, losing 2-1 at home to Burton Albion.
Midfielder Neal Bishop's 34th minute strike condemned Blackburn to a 1-0 home loss to Scunthorpe United, while Northampton Town earned a thrilling 3-2 success at Wolves.
But each of those results were dwarfed by events at Victoria Road, where Dagenham suffered spot-kick agony after an astounding encounter despite Ashley Hemmings' double.
Leyton Orient also went through 6-5 on penalties following a 3-3 draw with a spirited Plymouth Argyle side.
Ipswich Town were another second-tier side to exit as Izale McLeod's 111th minute effort sealed a 1-0 win for Crawley Town, and beleaguered Blackpool were defeated 1-0 by Shrewsbury Town.
Managerless Huddersfield Town staged a dramatic comeback to beat Chesterfield 5-3 in their first game since the departure of Mark Robins.
Trailing 3-1 with six minutes remaining, the visitors scored two late goals through Nahki Wells and Jon Stead before the former completed his hat-trick to help cap the turnaround in extra time.
Birmingham City needed extra time to beat Cambridge United 3-1, while Bolton Wanderers came from behind to beat Bury 3-2 in 120 minutes.
Rotherham United required the extra 30 minutes to beat Fleetwood Town 1-0 but the majority of Championship teams all progressed with no such difficulties.
Middlesbrough, Sheffield Wednesday, Nottingham Forest, Brighton and Hove Albion, Bournemouth, Watford and Reading all enjoyed relatively straightforward routes into the next round.
Leeds United were 2-1 winners over Accrington Stanley and Millwall knocked out Wycombe Wanderers 1-0 in outings that each saw the Championship side reduced to 10 men.
Ben Williamson scored a hat-trick as Hartlepool United were hammered 6-2 by Port Vale, whose League One counterparts Preston North End, Crewe Alexandra, Doncaster Rovers, Swindon Town, Charlton Athletic, Gillingham, Walsall and Milton Keynes Dons all emerged victorious.
Bristol City and Peterborough United each suffered surprise losses to Oxford United and Portsmouth respectively, while Bradford City won 1-0 at Morecambe.
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