The victory was England's first in a test against Australia at Lord's in 75 years.
Flintoff, bowling through pain in his right knee that led him to announce that he will retire from tests after this series, finished with figures of 5-92. He bowled ten consecutive overs from the start of play to earn his third five-wicket haul in tests.
"It's been a good test match," Flintoff, named man of the match, said. "It's nice to take five (wickets) on the last morning and receive all the plaudits but it's been a team effort."
"There might be occasions when I'm feeling tired or aching but Straussy (captain Andrew Strauss) was never going to get the ball out of my hand," he added. "I have got three test matches left and I will give my all. It's going to be hard to get through them but I will be giving everything."
Off-spinner Graeme Swann had 4-87 and removed Michael Clarke, who made 136 and was Australia's main hope in an attempt to reach a record run chase total of 522. Australia, seeking to retain the Ashes, was eventually dismissed for 406 with Mitchell Johnson contributing 63 from 75 balls.
England heads to Edgbaston for the third test on July 30 intent on keeping its lead in the series.
The hosts were humiliated in the 2006-07 Ashes series, losing by a 5-0 margin. This series started differently when the first test in Cardiff was drawn after a battling match-saving effort by England.
"We have enjoyed playing here (Lord's) and have a proud record over a number of years so it's disappointing to lose any test match and especially here," Australia captain Ricky Ponting said.
James Anderson set an early positive tone for England with two lbw appeals in the first four balls of the day, though both were given not out by umpire Billy Doctrove.
Flintoff then claimed the first wicket of the morning before Australia had registered a run. Brad Haddin's resistance, which spanned 196 minutes, came to an end when he edged to Paul Collingwood at second slip for his overnight score of 80. The score was then 313-6.
Flintoff's bowling speeds were consistently above 90 mph and, to emphasize his threat, struck established batsman Clarke on the glove with a spiteful bouncer. The next ball swung into Clarke and cut away from the outside edge of his bat.
Johnson experienced similar hardship against Flintoff and was hit on the shoulder when he failed to connect with a hook shot when on 11. Two balls later he connected for one of his nine boundaries.
Johnson edged Stuart Broad towards Flintoff at second slip when on 15 but the ball just failed to carry and the batsman scrambled a single. Later in the same over, Clarke reasserted his authority by cover driving for a well-timed boundary.
Swann produced the key breakthrough by bowling Clarke, who had advanced down the pitch only to see the ball dip under his bat and spin back on to the off stump. Swann's ecstatic celebration illustrated the team's relief at removing Clarke.
Australia's vice-captain batted for 319 minutes, faced 227 deliveries and struck 14 boundaries.
Nathan Hauritz (1) was bowled by Flintoff after offering no stroke and Peter Siddle was also bowled by the Lancashire all-rounder, who celebrated his fifth wicket with his usual modesty, kneeling on the Lord's turf and acknowledging the applause.
Scoreboard:
England 1st innings
Andrew Strauss b Hilfenhaus 161
Alastair Cook lbw b Johnson 95
Ravi Bopara lbw b Hilfenhaus 18
Kevin Pietersen c Haddin b Siddle 32
Paul Collingwood c Siddle b Clarke 16
Matt Prior b Johnson 8
Andrew Flintoff c Ponting b Hilfenhaus 4
Stuart Broad b Hilfenhaus 16
Graeme Swann c Ponting b Siddle 4
James Anderson c Hussey b Johnson 29
Graham Onions not out 17
Extras: (15b, 2lb, 8nb) 25
TOTAL: (all out) 425
Overs: 101.4.
Fall of wickets: 1-196, 2-222, 3-267, 4-302, 5-317, 6-333, 7-364, 8-370, 9-378.
Bowling: Ben Hilfenhaus 31-12-103-4 (4nb), Mitchell Johnson 21.4-2-132-3, Peter Siddle 20-1-76-2 (4nb), Nathan Hauritz 8.3-1-26-0, Marcus North 16.3-2-59-0. Michael Clarke 4-1-12-1.
Australia 1st innings
Phillip Hughes c Prior b Anderson 4
Simon Katich c Broad b Onions 48
Ricky Ponting c Strauss b Anderson 2
Mike Hussey b Flintoff 51
Michael Clarke c Cook b Anderson 1
Marcus North b Anderson 0
Brad Haddin c Cook b Broad 28
Mitchell Johnson c Cook b Broad 4
Nathan Hauritz c Collingwood b Onions 24
Peter Siddle c Strauss b Onions 35
Ben Hilfenhaus not out 6
Extras: (4b, 6lb, 2nb) 12
TOTAL: (all out) 215
Overs: 63.
Fall of wickets: 1-4, 2-10, 3-103, 4-111, 5-111, 6-139, 7-148, 8-152, 9-196.
Bowling: James Anderson 21-5-55-4, Andrew Flintoff 12-4-27-1 (2nb), Stuart Broad 18-1-78-2, Graham Onions 11-1-41-3, Graeme Swann 1-0-4-0.
England 2nd innings
Andrew Strauss c Clarke b Hauritz 32
Alastair Cook lbw b Hauritz 32
Ravi Bopara c Katich b Hauritz 27
Kevin Pietersen c Haddin b Siddle 44
Paul Collingwood v Haddin b Siddle 54
Matt Prior run out 61
Andrew Flintoff not out 30
Stuart Broad not out 0
Extras: (16b, 9lb, 5nb, 1w) 31
TOTAL: (for six wickets declared) 311
Overs: 71.2.
Fall of wickets: 1-61, 2-74, 3-147, 4-174, 5-260.
Still to bat: Graeme Swann, James Anderson, Graham Onions.
Bowling: Ben Hilfenhaus 19-5-59-0 (3nb), Mitchell Johnson 17-2-68-0 (1w, 1nb), Peter Siddle 15.2-4-64-2, Nathan Hauritz 16-1-80-3 (1nb), Michael Clarke 4-0-15-0.
Australia 2nd innings
(overnight 313-5)
Phillip Hughes c Strauss b Flintoff 17
Simon Katich c Pietersen b Flintoff 6
Ricky Ponting b Broad 38
Mike Hussey c Collingwood b Swann 27
Michael Clarke b Swann 136
Marcus North b Swann 6
Brad Haddin c Collingwood b Flintoff 80
Mitchell Johnson b Swann 63
Nathan Hauritz b Flintoff 1
Peter Siddle b Flintoff 7
Ben Hilfenhaus not out 4
Extras: (8lb, 5b, 8nb) 21
TOTAL: (all out) 406
Overs: 107.
Fall of wickets: 1-17, 2-34, 3-78, 4-120, 5-128, 6-313, 7-356, 8-363, 9-388.
Bowling: James Anderson 21-4-86-0, Andrew Flintoff 27-4-92-5 (8nb), Graham Onions 9-0-50-0, Stuart Broad 16-3-49-1, Graeme Swann 28-3-87-4, Paul Collingwood 6-1-29-0.
Toss: England.
Result: England won by 115 runs.
Umpires: Rudi Koertzen, South Africa and Billy Doctrove, Dominica.
