Cameron Smith and Matty Johns have agreed on who they feel will make the 2021 NRL Grand Final with two sides clear favourites to make the decider.

The pair hypothesised that Melbourne and South Sydney will be the team battling it out for the premiership on October 3 off the back of the Rabbitohs' upset win over Penrith in week one.

Both sides have had strong home-and-away seasons with the former taking out the minor premiership and coming tantalisingly close to achieving an historic 20 wins in a row.

The Rabbitohs finished in third place, four wins clear of fourth-placed Manly and last week outlasted Penrith to set up a home preliminary final date against the winner of the Sea Eagles and Roosters semi.

Speaking on SEN 1170 Breakfast, Melbourne Storm legend Cam Smith explained that it would take something extraordinary to prevent his prediction from coming to fruition.

"I think it’s Melbourne and the Rabbitohs,” Smith said.

“I think it’s pretty clear cut now, after the loss on the weekend, Penrith will have to play their absolute best game of the season to reach a Grand Final.

“Firstly, they’ve got to get through Parramatta, then they’ll have to go through Melbourne who were red hot on Friday night.

“Then the Rabbits, they looked so composed, they played a solid style of football that works so well in finals.

“I don’t see either of the Roosters or Manly beating the Rabbitohs after what I saw on the weekend.”

Smith's former side comprehensively defeated Manly on the Gold Coast last Friday evening, beating Des Hasler's side 40-12.

Ryan Papenhuyzen had a night to remember as he scored two tries and ran the show for Craig Bellamy's side to book a preliminary final spot against Parramatta or Penrith.

Matty Johns on the other side of the panel highlighted how the Souths knocking off Penrith 16-10 on Saturday night has turned the narrative of finals on it's head.

“I said the loser of Melbourne and Manly couldn’t rebound to win the comp, but that was purely off if Penrith won in week one, I couldn’t see [South Sydney] beating the Panthers,” Johns said.

“But after that game, it’s really changed a lot of stuff.

Johns also noted the weeks break that Melbourne and the Rabbitohs have and how it should play into their hands - especially in another COVID-marred finals series.

“We used to think all the time whether it was better to have the week off, or keep playing to gain momentum,” the Newcastle legend said.

“It’s undeniable now that the advantage the week off gives you.

“For that reason, I’m with Cameron, I’m with Souths, and they’ll play Melbourne."

The semi-finals kick off this week with Manly and Sydney doing battle on Friday night in Mackay.

The other fixture sees the Panthers going up against the Eels at the same venue with Penrith going in as clear favourites, especially considering their previous victory over Parramatta in Round 25 which ended 40-6.