Newcastle received a boost before the contest after it was revealed that Anthony Gordon and Isak had proved their fitness in time for the lunchtime kickoff.
Their inclusion ultimately proved to be crucial as Isak required just 10 minutes to head Newcastle into the lead from an inviting Gordon cross.
After going behind, Arsenal threatened to restore parity before the break, only to see Mikel Merino's effort kept out by Lewis Hall's last-ditch block.
Declan Rice then went close with Arsenal's first chance of the second period, sending his deflected strike just wide of Nick Pope's far post.
While the Gunners may have threatened on a couple of occasions, they ultimately lacked a real cutting edge as they struggled to find their best form at St James' Park.
Arsenal's disappointing display was summed up when Rice spurned a golden opportunity in stoppage time, directing his header wide from Bukayo Saka's inswinging cross.
In contrast to their hosts, Newcastle celebrated a successful day and their first Premier League win since September 15.
The win move the Magpies up to eighth place for the time being, while Arsenal could find themselves eight points adrift of top spot if Manchester City beat Bournemouth.
NEWCASTLE VS. ARSENAL HIGHLIGHTS
Isak goal vs. Arsenal (10th min, Newcastle 1-0 Arsenal)
Newcastle take the lead at St. James Park. Sean Longstaff plays the ball out to the right flank for Gordon to whip an inch-perfect delivery onto Isak's head. The Sweden international powers his header past Raya to score in back-to-back league games.
MAN OF THE MATCH - LEWIS HALL
There were a number of impressive displays in a Newcastle shirt, but Hall was arguably the home side's standout performer.
The left-back did a stellar job of negating Saka's attacking threat and also made a crucial block to deny Merino in the first half.
Hall won three of his four tackles, made three blocks, eight clearances and seven recoveries during a resolute display in Newcastle's backline
NEWCASTLE VS. ARSENAL MATCH STATS
Possession: Newcastle 36%-64% Arsenal
Shots: Newcastle 9-10 Arsenal
Shots on target: Newcastle 4-1 Arsenal
Corners: Newcastle 4-6 Arsenal
Fouls: Newcastle 16-18 Arsenal
BEST STATS
WHAT NEXT?
After claiming a much-needed league win, Newcastle will now turn their focus to next Sunday's away meeting with Nottingham Forest.
As for Arsenal, they travel to Italy for a midweek Champions League clash with Inter Milan, before they face Chelsea in their final game before the international break.