Fernando Santos's side have taken seven points from a possible nine to sit at the top of the group, whereas the visitors to the Estadio Algarve lost both of their opening fixtures in March.
Match preview
Defending their continental crown was always going to be an uphill battle for Portugal - especially seeing as they were placed in the group of death with France and Germany at Euro 2020 - but the 2016 champions managed to advance in third place and set up a tantalising last-16 battle with Belgium.
However, Santos's crop - who only managed to beat Hungary in the group stage - were undone by a Thorgan Hazard winner and bowed out with a whimper, but Cristiano Ronaldo was at least able to add to his ever-growing haul of personal accolades by becoming the all-time top goalscorer in European Championship history.
Should the soon-to-be Manchester United returnee make the net ripple as expected in September, he will surpass Iran's Ali Daei as the highest scoring international player in history, but more importantly take Portugal one step closer to the promised land of Qatar.
Despite having to share the spoils in a 2-2 draw with Serbia, Portugal's victories over Azerbaijan and Luxembourg in Group A saw them rise to the summit after the opening round of qualifying fixtures, although they only sit above their Serbian counterparts on goal difference.
A friendly battle with host nation Qatar follows for Portugal before they round off this international period against Azerbaijan, and barring any disasters, a straightforward path to a sixth successive appearance in the World Cup Finals should follow.
After a painful 11 games without a win to his name in the Ireland dugout, Stephen Kenny finally had something to cheer in June's friendly fixtures, with his Ireland outfit getting the better of Andorra 4-1 in a friendly before drawing 0-0 with Hungary in their most recent match.
However, as far as competitive action goes, the Boys in Green have flattered to deceive. After ending a Nations League campaign without a win to their name, Ireland sought to make amends in World Cup qualifying, but two opening defeats means that Kenny's men have already been cut adrift of the Qatar hopefuls.
The Boys in Green had their moments against an Aleksandar Mitrovic-inspired Serbia but ultimately went down 3-2 on the opening matchday, and in an encounter labelled "embarrassing" by captain Seamus Coleman, Ireland then lost 1-0 to Luxembourg as the alarm bells started ringing louder.
Nevertheless, Ireland have stuck by Kenny - in spite of his underwhelming record of one win in 13 games in charge - but any hopes of a first World Cup proper appearance since 2002 are already hanging by a thread before they meet Ronaldo and co.
Portugal have only won one of their last four games with Ireland in all competitions, although it was the most recent one - a 5-1 friendly thrashing in 2014 - and the two sides played out two 1-1 draws during qualification for the 2002 World Cup.
Portugal World Cup Qualifying - Europe form:
Portugal form (all competitions):
Republic of Ireland World Cup Qualifying - Europe form:
Republic of Ireland form (all competitions):
Team News
Ricardo Pereira's long road back to international football is set to continue a little while longer following his hamstring injury at the weekend, while Euro 2020 contingent William Carvalho, Joao Felix, Renato Sanches and Jose Fonte are nowhere to be seen either.
Uncapped trio Diogo Costa, Otavio and Goncalo Inacio may have to wait until the friendly with Qatar to make their international debuts, while Ronaldo will have his sights set on that record-breaking 110th international goal.
Pepe - still going strong at 38 - will hope to resume his partnership with Ruben Dias at the back, with Bernardo Silva and Diogo Jota providing support to talisman Ronaldo in the final third.
Meanwhile, Ireland have welcomed uncapped defenders Nathan Collins and Andrew Omobamidele to the group for the first time, but James McCarthy and Robbie Brady will not be involved.
Experienced goalkeeper Darren Randolph has also been left out, meaning that Kenny must choose between international novices Gavin Bazunu, Mark Travers and Caoimhin Kelleher, who boast eight caps between them.
Kenny will have to work around fatigue for further clashes with Azerbaijan and Serbia, and the visiting boss could stick with the three-man defensive setup from March's fixtures, with the reinvigorated Shane Duffy doing his best to quell the threat of Ronaldo.
Portugal possible starting lineup:
Patricio; Cancelo, Pepe, Dias, Guerreiro; Pereira, Moutinho, Fernandes; B. Silva, Ronaldo, Jota
Republic of Ireland possible starting lineup:
Kelleher; Egan, Duffy, O'Shea; Doherty, Hendrick, Hourihane, Cullen, McClean; Connolly, Idah
We say: Portugal 2-0 Republic of Ireland
Seeking to bounce back straight away from a disappointing Euro 2020 campaign, Portugal are obviously the overwhelming favourites to get the job done on home soil and should have no problem doing so.
Kenny's Ireland are starting to show some signs of new-found resilience, but that is sure to be broken here, especially with Ronaldo setting his sights on yet another individual record to shatter.