West Indies raced to 83 without loss at tea on Friday after some poor home bowling as they faced the daunting task of replying to England's highest total against the tourists at Lord's.
Giles came to the fore after the interval, however, first slowing the run rate with some neat bowling and then taking two wickets in four balls.
First Devon Smith played on for 45 and then Chris Gayle, who had looked well set, was adjudged lbw for 66 playing a sweep.
Matthew Hoggard weighed in with the wicket of Ramnaresh Sarwan, lbw for one. Hoggard was the first to utilise the famous slope and make the ball nip back.
Giles went on to remove an annoyed Brian Lara for 11, West Indies' captain given out by Daryl Harper for a faint edge to wicketkeeper Geraint Jones.
However, he could equally have been dismissed lbw as the ball brushed his pad before Jones gathered.
Giles, so often criticised for negative tactics, bowled 20 overs for 58 runs as he became England's main strike bowler for the day, upstaging world number two Steve Harmison who went for 42 runs from nine overs.
At the close Shivnarine Chanderpaul was 41 not out with Dwayne Bravo on 30.
ELEGANT GLANCE
England should earlier have scored well over 600 but lost their last seven wickets for 41 runs in 68 balls with Pedro Collins grabbing four wickets for 16 runs in 21 deliveries.
The collapse did not deny captain Michael Vaughan a 12th Test century however, stroking 12 fours in his 103 before edging Collins to Smith in the slips.
Key had earlier reached 200 with an elegant glance off his legs which brought up his 29th four. He struck two more boundaries but was out for 221, the third-highest score by an England player at Lord's, cutting debutant Bravo to Lara for the bowler's first Test wicket.
The 25-year-old Key, who had resumed on 167 not out, left the field to a rousing reception at a packed and humid Lord's after facing only 288 balls.
England began on 391 for two after Thursday's record 291-run stand between Key and Andrew Strauss, who made 137.
Not since 1990 have three English batsmen scored centuries in the same innings.
West Indies fielding was again sub-standard and they conceded 48 extras, although Bravo, three for 74 on his debut, deserved much credit.
Scoreboard
England first innings (overnight 391-2)
M.Trescothick c Sarwan b Best 16
A.Strauss c Jacobs b Banks 137
R.Key c Lara b Bravo 221
M.Vaughan c Smith b Collins 103
G.Thorpe c Jacobs b Bravo 19
A.Flintoff b Banks 6
G.Jones c Jacobs b Collins 4
A.Giles c Smith b Collins 5
M.Hoggard not out 1
S.Jones lbw b Collins 4
S.Harmison b Bravo 4
Extras (b-2, lb-20, w-13, nb-13) 48
Total (all out, 121.4 overs) 568
Fall of wickets: 1-29 2-320 3-485 4-527 5-534 6-541 7-551 8-557 9-563
Bowling: Collins 24-2-113-4 (nb-6, w-1), Best 21-1-104-1 (w-1), Edwards 21-2-96-0 (nb-6, w-3), Bravo 24.4-5-74-3 (w-4), Banks 22-3-131-2 (nb-1), Sarwan 9-0-28-0
West Indies first innings
C.Gayle lbw b Giles 66
D.Smith b Giles 45
R.Sarwan lbw b Hoggard 1
B.Lara c G.Jones b Giles 11
S.Chanderpaul not out 41
D.Bravo not out 30
Extras (b-4 lb-8 nb-2) 14
Total (for four wickets, 51 overs) 208
Fall of wickets: 1-118 2-119 3-127 4-139
To bat: R.Jacobs, O.Banks, P.Collins, T.Best, F.Edwards.
Bowling: Hoggard 51-2-57-1, Harmison 9-2-42-0, S.Jones 7-1-39-0 (nb-2), Giles 20-3-58-3
