While Houston starter RHP Roy Oswalt gave up a walk to CF-L Jim Edmonds in the bottom of the first, Edmonds was the only baserunner allowed by either Oswalt or St. Louis starter LHP Mark Mulder in the first two innings of Game 6 of the NLCS. Leading off the top of the third, C-R Brad Ausmus produced the first hit of the game, sending a grounder into left field for a single. SS-R Adam Everett then hit a grounder past a diving 1B-R Albert Pujols to the edge of the infield for a single that advanced Ausmus to second. Oswalt executed a successful sacrifice bunt in order to move the runners to second and third. Mulder's first pitch to 2B-R Craig Biggio went wild hitting the dirt in the box behind Biggio and escaping C-R Yadier Molina. Ausmus came home on the wild pitch. Biggio then hit a line drive into left for a single that drove in Everett to put the Astros up 2-0. Mulder prevented Houston from building on that lead, but while Oswalt hit SS-R David Eckstein with an inside pitch in the bottom of the third, St. Louis was unable even to muster another baserunner in the third.

One out into the top of the fourth, RF-R Jason Lane whacked the ball into the left field stands to increase the Astros' lead to 3-0. Ausmus hit a line drive into right field for a single, but Houston did not score again in the inning. Oswalt went one-two-three through the heart of the Cardinals' order in the bottom of the fourth.

Both Oswalt and Biggio hit long but catchable fly balls into the outfield for the first two outs of the top of the fifth. CF-R Willy Taveras then hit a groundball past a diving Eckstein into shallow center for a single. Mulder's first pitch to Berkman was high and outside and Molina failed to get his glove on it, so Taveras took second while Molina retrieved the wild pitch. After Mulder issued a four-pitch walk to Berkman, St. Louis called for RHP Brad Thompson to relieve him. When the game resumed, 3B-R Morgan Ensberg popped out to end the inning with the runners stranded at first and second.

In the bottom of the fifth, Oswalt an inside pitch came in and hit lead off hitter 2B-R Mark Grudzielanek on the hands, giving him first base. Molina hit a line drive into shallow right field for a single that moved Grudzielanek to second. Up next, 3B-S Abraham Nunez hit a grounder up the middle. Oswalt bobbled the ball before throwing to second where Everett had to lunge off the bag toward first to make the catch. As he fell, Everett swiped at Molina, who was coming into second and from the camera angle in front of second it looked as though Molina was out. The umpire was in position in front of second and called Molina out, but replays from a side angle clearly show Everett's tag missing Molina by several inches. While Molina and manager Tony LaRussa argued the decision, the call stuck, and play continued. With runners on first and third, left-handed hitter John Rodriguez, who was pinch-hitting for Thompson hit a flyball into center, where Taveras made the catch. However, Grudzielanek was able to tag up and come home to give the Cardinals' their first run of the game. Eckstein struck out, ending the inning before St. Louis could further narrow the gap.

RHP Jason Marquis took the mound for St. Louis in the top of the sixth. One out into the inning, LF-R Chris Burke hit a grounder into left field for a single. Ausmus then hit a line drive into shallow right field for a single that moved Burke to third. Burke was running when Everett bunted down the third base line, pulling off a suicide squeeze to increase Houston's lead to 4-1. The inning ended with Oswalt striking out, but the exertion of batting didn't harm his effectiveness. RF-L Larry Walker hit a line drive into the right field corner for a double, but the meat of the Cardinals' lineup produced no other baserunners.

Biggio led off the top of the seventh with a grounder into left field for a single. Taveras laid down a sacrifice bunt to advance Biggio to second. St. Louis brought in LHP Randy Flores to pitch to Berkman and then switched to RHP Julian Tavarez after Berkman hit a flyball to Walker on the line in right field. Facing Tavarez, Ensberg hit a line drive up the middle into centerfield. The ball bounced past the glove of Edmonds, who was coming in to field it, and while Edmonds retrieved the ball, Biggio went home to make the score 5-1 Astros, and Ensberg went to second on the error. With Lane at the plate, Tavarez bounced a ball in the dirt on the far right side of the batter's box, allowing Ensberg to advance to third on the wild pitch. However, Lane grounded out to end the inning rather than driving in Ensberg. In the bottom of the seventh, Nunez hit a line drive up the middle for a single, but Oswalt did not allow the Cardinals any other baserunners.

Tavarez pitched an effective one-two-three eighth for St. Louis, and Houston sent RHP Chad Qualls out for the bottom of the inning. Qualls likewise kept the Cardinals off the bases in the eighth. RHP Jason Isringhausen received the ball for St. Louis in the top of the ninth. Isringhausen gave up a line drive single to Taveras but otherwise held the Houston offense in check, giving the Cardinals a shot at a comeback in the bottom of the ninth.

The Astros opted not to go to closer RHP Brad Lidge for the ninth and instead sent RHP Dan Wheeler to the mound. Wheeler struck out both Walker and LF-L John Mabry before allowing Grudzielanek to hit a line drive single into left field. Nevertheless, there was no stunning comeback like that in Game 5 of the series. Molina hit a fly ball into right field, where Lane made the catch to end the game, sending Houston to the World Series for the first time in the history of the franchise. The Astros will also be the first Texas team to participate in a World Series.

Oswalt received the NLCS MVP. Oswalt won both of the games he started, amassing a 12:4 K:BB with 8 H and 1 HR allowed in 14 IP for a 1.29 ERA.