England will go on to face Australia, South Africa and world champions New Zealand over successive weekends at Twickenham and must retain their fourth-place ranking to be seeded for the 2015 World Cup when the pool draw is made on December 3.
Lancaster has named one of the most inexperienced England sides in the professional era to tackle the Fijians, with Leicester hooker Tom Youngs making his Test debut.
Eleven of England's starting side go into the match with 13 caps or fewer, but Lancaster has called on them to deliver a complete performance against the Pacific islanders.
"This is the start of a huge four-week journey for us that will test us in every way," Lancaster said. "It is about putting a marker down at the start of this series."
There are a total of five changes from the 14-14 draw with South Africa in the summer, with Chris Robshaw back to captain the side after missing that Test with a broken hand.
Tom Johnson and Thomas Waldrom continue in the back row after making their Test debuts on the summer tour, while Tom Wood returns to the fold after 14 injury-plagued months with a place on the bench.
Alex Goode continues at full-back while Brad Barritt and Manu Tuilagi link up in a hard-hitting centre partnership, with the half-backs of Toby Flood and Danny Care the most experienced unit in the team.
Ugo Monye will make his England comeback on the left wing in place of the injured Ben Foden, while Charlie Sharples will deputise for the suspended Chris Ashton on the right wing.
The uncapped pair of Saracens prop Mako Vunipola and Wasps lock Joe Launchbury are primed to make their Test debuts off the bench.
Flood (50), Care (33), Tom Palmer (40) and Dan Cole (31) account for 154 of the 215 caps in England's starting line-up.
To put that in context, when England started with three debutants in Lancaster's first game against Scotland in February it was still a more experienced side than this one, with a combined total of 236 caps.
"As you can see from selection, there is a lot of consistency from the South Africa tour, particularly the team that played in the last Test, which is based on form in the Premiership," Lancaster said.
"There are some new players coming in. It is great to get Tom Young involved and I am excited to see what Mako Vunipola and Joe Launchbury could do off the bench."
Tom and Ben Youngs, who is on the bench as scrum-half back-up for Danny Care, could become the first brothers to play together for England since Delon and Steffon Armitage in 2009.
Tom Youngs' selection may have been predicated by Dylan Hartley's injury but it completes a remarkable rise for the 25-year-old, who has made just seven Aviva Premiership starts at hooker.
Youngs played England age-group rugby as a hard-hitting centre and was on the fringes of the Leicester side when Tigers director of rugby Heyneke Meyer suggested he should become a hooker.
The conversation occurred after Youngs had been involved in a mass brawl while captaining the Leicester second team against Saracens.
That was three years ago. Youngs went out on loan to Nottingham to learn his new trade and caught the eye of England's forwards coach Graham Rowntree.
Youngs toured with England in the summer, playing two midweek matches, before returning to Leicester and establishing himself as first-choice hooker.
"There are not many centres who transfer from hooker so mental resilience and toughness is one of his strengths," Lancaster added.
"So too are his physicality, his handling, his defence and his set piece. He has areas to work on but the scrum power he brings is phenomenal.
"People make a lot of his throwing but he has done it consistently in big games."
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