The Spain international was the star of the show and netted either side of half-time, but again Real looked to be lacking their usual bite, even with talisman Cristiano Ronaldo in the starting lineup for the third straight league game.
Los Blancos are still playing catch-up with Barca, who reclaimed a five-point lead at the head of the table earlier on Sunday, overcoming a slow start in front of an empty Camp Nou to beat Las Palmas 3-0.
Achraf Hakimi got the nod at right-back in the place of injured Dani Carvajal, while Nacho started on the other side of defence with Marcelo also out of contention due to injury.
The opening exchange of Sunday's meeting at the Estadio Santiago Bernabeu was as one-sided as one is likely to see at this level. WhoScored.com stated Real boasted close to 70 per cent possession in the first 20 minutes.
Sergio Ramos came within centimetres of breaking the deadlock when he fired a header in the direction of Pau Lopez, only for the Espanyol goalkeeper to tip it over the bar. Isco made up for that close call minutes later.
On the half-hour mark, Ronaldo drew his markers to the left edge of Espanyol's box before threading Isco in for a one-on-one finish, which Squawka pointed out as a landmark assist for the Portuguese:
It seemed almost inevitable that the political discourse of the day would also find its way into Sunday's clash, with BBC News reporting 761 people were injured by police attempting to stop the voting in the Catalan referendum.
Ben Hayward of Goal provided a glimpse of the Bernabeu's reaction to Isco's breakthrough:
Real were the major aggressors in the first half, but a cushion of only one goal wasn't the advantage they sought and was in danger of being toppled as long as it remained that way.
In fact, ESPN FC's Dermot Corrigan hinted at Espanyol's contention at the half-time interval, suggesting the visiting team might have been level with their hosts had more luck been on their side:
Gerard Moreno hitting the woodwork near the half-time whistle was as close as Espanyol came to piercing Real's lines in the first period, although they did pop up with their chances after the interval, too.
Manager Zinedine Zidane finally got the reprieve he sought when Isco fired in a second with 20 minutes remaining to ease the tensions, picking his spot brilliantly after an exchange with the lively Marco Asensio, per Yahoo's Andrew Gaffney:
That strike gave the hosts the breathing space they needed to settle the nerves, and again Real looked to be lacking that extra bit of confidence or lethal edge that's been so evident over the past two years or so.
One positive Zidane can take from Sunday's encounter is the increased youth involvement in his squad, with the likes of Dani Ceballos and Lucas Vazquez coming on to feature in the second half.
Victory on Sunday means Real have won back-to-back league games for the first time this season, and while that may have seemed minor in recent years, every win will be cherished given the team's current standing.
The international break may be seen as well-timed for Real in that regard, giving Zidane a fortnight to reassess their start to the campaign ahead of their trip to Getafe on October 14.