The defeat was compounded by a possible knee injury to Chris Lawrence, who collided legs with Josh Mansour midway through the second half and failed to return.
The home side conceded first points when Mitchell Moses broke through and found a flying Josh Addo-Carr to claim his fifth try in just seven NRL appearances.
However, the Panthers quickly hit back through Blake, and then poured on the points through Bryce Cartwright (18th minute), Isaah Yeo (24th), Reagan Campbell-Gillard (29th) and Peter Wallace (39th).
Blake scored after a 60-metre break by Dallin Watene-Zelezniak, who took a pass from Matt Moylan in front of his own posts and then burned Tim Simona to surge downfield.
By halftime, the Tigers had missed 30 tackles to Penrith's eight, given up 64 per cent possession and were on the wrong end of a 28-4 deficit.
The Panthers' momentum failed to halt after the break, with Trent Merrin and James Fisher-Harris crossing inside the hour mark to put the result beyond the Tigers' reach.
Moses, who was arguably the Tigers' best, scored a consolation try in the 63rd minute. Tigers prop Tim Grant could find himself in trouble for a high shot on Watene-Zelezniak in the first half despite not being placed on report.
Penrith coach Anthony Griffin was happier with his team's defence than their attack, particularly in the second half, to keep the Tigers to just 10 points.
"Even though we had the game in hand, our defensive effort was the closest to an 80-minute one that we've had. We're learning," he said.
"A few weeks ago we might've lost control of that last 20 minutes, even though it got a bit scrappy. We had composure with the ball and defensively as well."
Tigers coach Jason Taylor said his players were distraught.
"We've got a really shattered group of players in the rooms. Some inconsolable, to be honest. Such a disappointing performance," he said.
Taylor was also at a loss to explain why they gave up so many points in the first half.
"The start itself was fine, but then we just took some short cuts. The only thing I can put that down to was just a lack of energy that was required to go with Penrith in the first half," he said.
"We just don't do that any more. We got that stuff out of our game and it's been great to watch. But it came back tonight. It was really disappointing."
- AAP