Nathan Delfouneso had put the Tangerines ahead with just their second goal of the campaign, but Alex Pritchard levelled things up after 37 minutes before Stuart Dallas’ goal seven minutes into the second half earned the Bees their opening win on their return to the second tier after 21 years.
The result left Blackpool with just one win from their last 13 games in all competitions, and without a Championship point this term.
In front of a far-from-capacity crowd, the first chance fell to the home side as Donervorn Daniels rose highest to greet a left-wing corner in the fourth minute, but headed over the bar from six yards.
Jose Riga’s side threatened again in the eighth minute, as Tony Craig’s clearance fell to Tomasz Cywka on the edge of the box but he saw his shot blocked, before John Lundstram fired wide from 20 yards.
Blackpool deservedly took the lead in the 17th minute as Delfouneso headed home from 12 yards from Francois Zoko’s left-wing cross – a move Delfouneso had started with a surging run from the halfway line.
Brentford began to get a foothold in the game but, despite forcing several corners and attacking set-pieces, failed to carve out any clear-cut chances.
Their pressure told, however, in the 37th minute through Pritchard, who latched onto Moses Odubajo’s lay-off and rifled the ball low to the right of Joe Lewis from 25 yards.
The visitors started the second half much the brighter and took the lead in the 52nd minute, Dallas pinching the ball off Daniels on the by-line and cutting inside from the left before firing past Lewis from a narrow angle.
Blackpool had their first effort of the second half in the 63rd minute, but David Perkins lash high over the bar from 25 yards.
The home side threatened again a minute later, as Tony McMahon struck a left-footed shot from the right of the area which was well pushed away by David Button in the Brentford goal.
Brentford almost put the game beyond the reach of Blackpool in the 76th minute when substitute Jota slid the ball across the six-yard area from the right, but it just evaded the onrushing Pritchard.
Blackpool introduced former Newcastle man Nile Ranger for his debut and he set up a golden chance for Sergei Zenjov to equalise six minutes from time, but Button denied him from six yards.
The home side continued their late push for an equaliser, Delfouneso firing over in the closing stages, but Brentford held firm to take all three points.