The hosts are aiming to improve on their last-16 finish in Russia 2018, whereas Greece are bidding to return to the world stage after missing out three years ago.
Spain will struggle to top their most recent result for a long time, as Luis Enrique's side hit Germany for six in the Nations League back in November on their way to a first-placed finish in League A Group 4, with Manchester City's Ferran Torres bagging an exceptional hat-trick on the night.
The 2010 World Cup champions have the Euros and a Nations League semi-final with Italy to look forward to later this year, but for now, Spain will simply be eyeing a comfortable route to Qatar as they seek to qualify for the finals for the 12th time running, last failing to do so in 1974.
However, their recent finishes in the world's most prestigious competition have been underwhelming to say the least, as they failed to advance past the group stage four years after their triumph in South Africa, while hosts Russia knocked Spain out on penalties in 2018.
Nevertheless, Enrique's side managed to prevail in all three of their home matches last year - keeping a clean sheet each time - and a 1-0 defeat to Ukraine was their only loss in their eight matches of 2020, so the Roja faithful will not be accepting anything less than a routine victory for their side this week.
Furthermore, the hosts will be eyeing their 10th successive victory on home soil this week, and having shipped just one goal in that time, Greece will have their work cut out for them if they are to prove their World Cup pedigree against the 2010 champions.
Greece have not exactly enjoyed a spate of success since their historic Euro 2004 triumph, and John van 't Schip's side failed to qualify for the continental championships for the second time in a row after winning just four of their 10 qualification matches in 2019.
Three of those wins came in their final three matches of the group, but by that time it was too little too late, and despite going unbeaten in their 2020-21 Nations League campaign, a record of three wins and three draws from six matches was not enough to see them pip Slovenia to top spot in League C Group 3 as they missed out on promotion to League B once again.
Van 't Schip's men demonstrated their defensive resilience with only one goal conceded in their six group matches in the Nations League, and they recorded shutouts four times on the bounce in the tournament, but three goalless stalemates brought attention to their lack of a clinical edge in the final third - something that must be rectified if they are to book a place in Qatar.
The visitors have lost just one of their last four away matches, although their successful results in that run came against Moldova and Kosovo, and with Sweden also vying for a place at the 2022 tournament, Greece are far from guaranteed to return to the World Cup after an eight-year absence, as Costa Rica knocked them out on penalties in 2014.
Spain and Greece have met eight times down the years, with the latter managing only one win in that time, and the most recent fixture between the two sides ended in a 2-1 win for Spain on their way to a Euro 2008 triumph.
While one Premier League goalkeeper in Kepa Arrizabalaga has been dropped from the squad, Brighton & Hove Albion's Robert Sanchez has earned his first call-up, but he is unlikely to challenge David de Gea for the number one spot.
Sergio Ramos has suffered yet another injury but is included in the squad despite his sprain, although Inigo Martinez and Diego Llorente could start at the back if no risks are taken over the 34-year-old's fitness.
Barcelona starlet Pedri has also been included in the squad for the first time but may not be trusted from the first whistle, while Torres could once again be supporting Alvaro Morata - who boasts a goal every other game for Spain - in the attack.
However, the more experienced Georgios Tzavellas and Kyriakos Papadopoulos may be preferred by Van 't Schip at the back, while Liverpool's Kostas Tsimikas will do battle with Norwich City loanee Dimitris Giannoulis for the left-back spot.
Kostas Fortounis is the top scorer in the squad with nine goals to his name, but his chances of hitting double figures against Spain are certainly slim, even if the inspirational Ramos does not start the match.
Spain possible starting lineup:
De Gea; Porro, Martinez, Llorente, Alba; Rodri, Thiago, Koke; Torres, Morata, Oyarzabal
Greece possible starting lineup:
Vlachodimos; Mavrias, Papadopoulos, Tzavellas, Giannoulis; Zeca, Bouchalakis; Limnios, Bakasetas, Fortounis; Pavlidis
We say: Spain 4-1 Greece
Spain's fearsome squad would strike fear into the hearts of most teams, and Enrique's side will certainly be favourites to progress as group winners as they prepare for an unrelenting year. The Roja's home record speaks for itself, and while Greece enjoyed a respectable Nations League campaign, they will be brought crashing back down to earth by Spain and we can only back a resounding home win this week.