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Club icon Simon Mannering was denied a fairytale finish to his career with the Panthers' victory at ANZ Stadium sending him into retirement and spoiling the Warriors' first playoff appearance in seven years.
Both Tuivasa-Sheck (ankle) and 301 game veteran Mannering (sternum) went into the game under an injury cloud and although the Warriors led 12-2 early on, their hopes of continuing a historic title run ended after their inspirational fullback was carried off with a medial knee injury 12 minutes before the break.
The Kiwi international's departure prompted a reshuffle with Peta Hiku filling in at fullback and Gerard Beale coming off the bench to slot in at right centre, but a try to five-eighth James Maloney and a double to right centre Tyrone Peachey gave Penrith an 18-12 halftime lead.
The Panthers set up camp on the Warriors' line after the resumption and extended their lead with a fourth try to right wing Christian Crichton, before Maloney banged over a field goal at the end of the third quarter.
Warriors halfback Shaun Johnson had a mixed night with some nice touches early on but their chances of a comeback were dashed when his attempted short drop-out gifted Penrith No 7 Nathan Cleary a penalty goal from in front to give them 25 unanswered points.
The Warriors showed courage to defend for long periods but poor ball control and ill-discipline saw them struggle for territory and momentum while the Panthers were clinical in completing their sets with Maloney orchestrating play with a brilliant kicking display.
Penrith opened the scoring off Cleary's boot but the Warriors hit back with hooker Issac Luke scoring their first try from dummy half and Johnson's conversion giving them a four point lead after 10 minutes.
A penalty helped the Warriors out of their half and their attack clicked into gear with front rower James Gavet offloading for Johnson who combined with Hiku before sending right wing David Fusitu'a in out wide as their lead grew to 12-2.
Things fell apart quickly however after an untimely error from senior forward Adam Blair with Maloney dragging Penrith back into the game with a 40-20 kick in the lead-up to Peachey's first try, before Luke sent the ball into touch from the restart to gift the them more attacking possession.
Penrith capitalised with Maloney backing up on the inside to run in their second four-pointer to give them a two-point advantage, before Peachey crossed for his second immediately following Tuivasa-Sheck's departure.
The Warriors clung on defensively for five straight sets early in the second-half but the pressure told with Crichton diving over out wide before Maloney's one-pointer and Cleary's fifth goal sealed the result.
There was still enough time for a Warriors comeback but the heavy defensive toll contributed to some frantic play that failed to threaten the Panthers defence.
Panthers 27 (Tyrone Peachey 2, James Maloney, Christian Crichton tries, cons, Nathan Cleary 3/4 cons, 2/2 pens, Maloney field goal)
Warriors 12 (Issac Luke, David Fusitu'a tries, Shaun Johnson 2/2 cons)