Bruno Guimarães had just levelled from the spot before, in the 85th minute, Dango Ouattara rifled beyond Nick Pope to nudge Brentford back in front.
The Brazilian had missed Newcastle United's last four matches with an ankle injury - and the Magpies had failed to win any of them. But he was back against Brentford and his ninth of the season has brought them back into this game.
Sven Botman scored on his 100th appearance for the club to give United the lead after 24 minutes, but Vitaly Janelt levelled matters and Igor Thiago put the visitors ahead just before half time.
Guimarães kept his nerve from the spot to level - but then Ouattara restored Brentford's lead.
The Magpies were seeking a first Premier League win since the dramatic 4-3 victory over Leeds United against a Bees side who had won four of their previous six in all competitions.
Harvey Barnes let fly inside three minutes but his effort was narrowly wide, then Sandro Tonali was off target from a free kick after Lewis Hall was fouled on the edge of the penalty area.
In the 15th minute, a Sandro Tonali corner was punched away by Caoimhin Kelleher as far as Jacob Murphy. His low drive was flicked goalwards by Barnes, but it went the wrong side of the post.
Then Mathias Jensen took advantage of a loose Jacob Murphy pass to stride towards the United box but Pope held his 20-yard strike.
But midway through the half, Botman opened the scoring. It was his third goal for the club and his first at St. James' Park as he celebrated a century of appearances in black and white.
Jensen had another opportunity for the visitors before superb play from Lewis Hall, with a bursting run and low cross, set up Yoane Wissa against his former club, but his shot was kneed off the line by Janelt.
And the German went on to head home from a brilliant Ouattara ball to equalise for his side.
Ouattara then cut the ball back for Jensen, whose shot was blocked by Murphy's arm from close range. The Newcastle man was unfortunate, and it look a lengthy VAR check to ascertain that it was indeed a handball, but Igor Thiago sent Pope the wrong way.
Howe made a double change at half time, with Nick Woltemade coming on to partner Wissa and Anthony Elanga also introduced, with Murphy and Joe Willock making way.
That led to a strong start to the second period from United, with Barnes heading downwards - but wide - from a Kieran Trippier cross.
William Osula then replaced Wissa as the Magpies continued to search for a leveller.
That almost arrived when Malick Thiaw carried the ball and unleashed a shot which was tipped away by Kelleher. Guimarães took the resulting corner, but it was headed into the side-netting by Botman.
But then came the equaliser. Osula broke swiftly and played in Elanga. Guimarães attacked his low cross and was hauled down by a clumsy Michael Kayode challenge.
And Guimarães stepped up to score from the spot and make it 2-2. United's joy was short lived, though, as Ouattara netted five minutes from time.
**Newcastle United:** Nick Pope, Kieran Trippier (Dan Burn 87), Lewis Hall, Sven Botman, Sandro Tonali (Jacob Ramsey 87), Yoane Wissa (William Osula 65), Harvey Barnes, Malick Thiaw, Jacob Murphy (Nick Woltemade 46), Joe Willock (Anthony Elanga 46), Bruno Guimarães (c)
**Subs not used:** Aaron Ramsdale, Alex Murphy, Leo Shahar, Sean Neave