The Real Madrid star was making his 110th international appearance and broke the deadlock 21 minutes in with his 48th goal for his country, overtaking Pauleta as Portugal's most-prolific player almost 10 years after scoring his first against Greece in Euro 2004.
Cameroon were in no mood to let sentiment get in the way, however, and equalised two minutes before the break as Vincent Aboubakar hit an emphatic finish under the helpless Beto.
Portugal should have retaken the lead on multiple occasions leading up to the hour mark, but found half-time substitute Guy N'Dy Assembe in good form between the post.
N'Dy Assembe, though, was powerless to prevent Portugal running riot in the last 25 minutes. Raul Meireles capitalised on a glaring defensive error before Fabio Coentrao, Edinho and Ronaldo wrapped up an easy win against a side who will join Portugal at the FIFA World Cup later this year.
Portugal coach Paulo Bento spoke prominently in the build-up regarding the integration of younger players to the national team and he subsequently gave debuts to 20-year-old pair Rafa Silva and Ivan Cavaleiro.
The hosts got off to a bright start in Leiria, with Meireles pulling the strings as he first set Rafa up to shoot straight at Charles Itandje following a cutback.
Cameroon's first chance of the match arrived in the 11th minute as Aboubakar burst in front of Rolando to meet a corner delivery, but Beto did well to keep the headed effort out to his left.
The visitors were made to regret that miss as Ronaldo gave Portugal the lead 10 minutes later.
Joao Pereira cut a precise pass back to Ronaldo on the edge of the area and, after a clever first touch to escape Nicolas N'Koulou, the Ballon d'Or winner drove his historic effort into the bottom-left corner.
Cameroon levelled just before the break, however.
Jean Makoun cleverly looped the ball over the Portugal defence for Aboubakar and all the Lorient man had to do was slot it under Beto.
Portugal appeared to have renewed enthusiasm after the break following a stuttering end to the first half and created several good opportunities
Itandje's half-time replacement – N'Dy Aseembe – was forced into action twice in quick succession in the 56th minute as he first palmed away Coentrao's half-volley before tipping a Ronaldo volley around the post.
Portugal eventually retook the lead 66 minutes in as Meireles pounced on a loose pass from Aurelien Chedjou to knock into an empty net before Coentrao made it 3-1 a minute later.
The Real Madrid man latched on to Cavaleiro's clever disguised pass in the left side of the area before dispatching with admirable composure.
A fourth arrived 10 minutes then. Ronaldo dazzled Allan Nyom with several stepovers before flashing a low ball across the face of goal and Edinho was on hand for an easy finish.
Four became five in the 83rd minute as the Cameroon defence failed to get Miguel Veloso's cutback under control and Ronaldo stole possession away before rifling a low shot past the goalkeeper.
