Defoe made his long-awaited return to the international arena, leading the side out alongside terminally-ill mascot and “best mate” Bradley Lowery, and grabbed his 20th Three Lions goal with a clinical first-half finish.
England did not put the result to bed until the 66th minute, when substitute Vardy made it 2-0 with his first touch of the match.
But a clean sheet left Gareth Southgate’s side as the only team in Europe yet to concede in World Cup qualifying.
Defoe said: “I enjoyed it. It’s been a good week, training’s been bright.
“It’s nice to score but just to win the game was important and we did that.
“It’s hard to put into words how I felt, just to be back and playing with the lads is a great feeling.
“Like I’ve always said, I’ll just get my head down and keep working hard and see what happens.”
Defoe returned to the England team for the first time since November 2013 as Southgate made four changes for his side’s World Cup qualifier against Lithuania at Wembley.
The Sunderland striker has scored 14 Premier League goals this season despite the Black Cats’ plight and replaced Jamie Vardy, who started the 1-0 defeat in Germany.
Michael Keane earned a first competitive cap alongside John Stones as Southgate reverted from three at the back to a flat four, with Raheem Sterling and Alex Oxlade-Chamberlain recalled.
Lithuania ceded ground to England from the off, sitting deep in defence with Nerijus Valskis alone in attack.
Dele Alli’s quick feet earned the hosts a promising free-kick when Arturas Zulpa lunged in but Engand’s chosen routine fell flat as Alli flicked Adam Lallana’s delivery tamely out of play.
Kyle Walker injected some energy in the eighth minute, commandeering a loose pass and charging through the centre of the field.
England had numbers in support but the Spurs full-back picked out a yellow shirt to his left, leaving Sterling to yell his disapproval in space on the right.
With the midfield area congested England had to work hard to find space, succeeding when Keane found Walker with a smart cross-field pass.
Walker did well to stretch and bring the ball under control before fizzing over a cross that was intercepted just in front of the lurking Defoe.
Lithuania goalkeeper Ernestas Setkus made a good save to deny Defoe after Lallana’s through ball but the veteran forward did not have to wait too much longer to celebrate.
With 22 minutes gone Sterling burrowed through on the left, cut the ball across the face of goal and found Defoe, who buried a rising shot for his 20th international strike.
The goal should have settled England but Lithuania almost took advantage of a brief lull in the immediate aftermath, captain Fedor Cernych spraying wide from 20 yards.
It was a momentary foray up the pitch and the previous patterns of English attack and Lithuanian defence quickly returned.
Defoe continued to be England’s focal point and fired a yard past the post when the ball dropped for him just outside the area.
After gently ushering the game towards the interval England almost conceded in the messiest of ways in added time. Vykintas Slivka won an innocuous header more than 30 yards from goal but his muscular connection almost caught Joe Hart out as Valskis, despite looking yards offside, read the bouncing ball better.
Hart managed an evasive parry under pressure and Stones backtracked to hook clear of the goalline.
After that shaky end to the first half England went close to re-establishing their superiority at the first possible opportunity.
The game had been back under way less than two minutes when Bertrand whipped a cross in from the left, finding Sterling at the far post. But the winger, enjoying a strong showing, could not sort out his feet and bundled his connection.
Lithuania were doing their best not to be passengers, Slivka giving Hart a gentle workout after Walker had been beaten on the right, but the emphasis was on England to settle things.
Oxlade-Chamberlain did his best when he ventured to the edge of the box and curled an effort towards the far corner but Setkus was equal to it and pulled off a sharp, diving save.
Southgate made a double change on the hour, sacrificing the creator and finisher of the only goal as Defoe and Sterling made way for Vardy and Marcus Rashford.
Rashford immediately put Lithuania on notice by dribbling past two men into the box and Leicester forward Vardy required just six minutes to put his name on the scoresheet.
Vardy produced a wonderfully calm finish to slot past Setkus but much of the heavy lifting came from a lovely pass off the instep of Lallana.