Alan McCormack's last-gasp winner extended play-off chasing Southend's unbeaten run to six league matches.
McCormack hit a right-foot shot that evaded Matt Glennon's reach - his third goal against Huddersfield this season.
Town thought they had salvaged a point when Andy Booth headed home Robbie Williams' corner with 17 minutes to go.
The impressive Tommy Black set up Hal Robson-Kanu for the opening goal after 40 minutes, the on-loan Reading winger curling home a left-foot shot.
Huddersfield: Glennon, Sinclair, Page, Clarke, Williams, Collins (Broadbent 78), Worthington (Berrett 86), Holdsworth, Brandon, Booth (Beckett 78), Kamara. Subs Not Used: Smithies, Hardy.
Booked: Page.
Goals: Booth 73.
Southend: Flahavan, Francis, Clarke, Barrett, Mulgrew (Grant 34), Black (Moussa 77), Bailey, McCormack, Gower, Walker, Robson-Kanu (Barnard 78). Subs Not Used: Scannell, Collis.
Booked: Grant.
Goals: Robson-Kanu 40, McCormack 90.
Att: 7,823
Ref: Mike Pike (Cumbria).
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