Former Essex batsman Owais Shah scored an unbeaten half-century as the Eagles slumped to their first T20 defeat of the season.
Shah and James Vince (57no) starred with the bat as Hampshire got to their target of 146 for the loss of just two wickets and with 16 balls to spare.
With two succesful - and impressive - run chases behind them already this season in the Natwest T20 Blast, the Eagles headed to the Ageas Bowl full of confidence.
But they will be disappointed to have only scored 145-5 after being asked to bat first.
Jesse Ryder fell for just one in the second over, and Essex's innings never really got going.
Tom Westley made 17 from 18 balls and Mark Pettini 29 from 33 to take the Eagles to 64-3 after 9.4 of their 20 overs.
In-form Ben Foakes made an impressive 43 from 34 balls and James Foster a run ball 29no, but the Eagles - even despite some good late hitting from Tim Phillips - managed only 10 fours and three sixes in their 20 overs.
One of those sixes came from the last ball, dispatched by Phillips, to close the innings in style.
Matt Salisbury gave the visitors the dream start in their defence of their 145-5 with a wicket maiden first up - having Michael Carberry caught by Foakes fourth ball.
But Vince and Jimmy Adams soon had the home side up above the asking rate, and even though Salisbury had Adams caught by Reece Topley for 32 in the fifth over, Hampshire cantered to victory.
Vince hit four fours and two sixes in his 47-ball knock, while Shah hit three fours and three sixes in his 35-ball 50no.
Salisbury was the clear pick of the bowlers with 2-23 from his four overs.
The Eagles' next T20 date is at the Oval against Surrey on Friday night, before they travel to Kent Spitfires the following Wednesday.
