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| Game | Date | Opponent | Result | Record | Venue | Recap |
|---|---|---|---|---|---|---|
| 1 | September 8 | Dallas Cowboys | W 19–10 | 1–0 | Reliant Stadium | Recap |
| 2 | September 7 | at Miami Dolphins | W 21–20 | 2–0 | Pro Player Stadium | Recap |
| 3 | September 12 | San Diego Chargers | L 20–27 | 2–1 | Reliant Stadium | Recap |
| 4 | September 11 | at Buffalo Bills | L 7–22 | 2–2 | Ralph Wilson Stadium | Recap |
| 5 | September 10 | Philadelphia Eagles | L 10–24 | 2–3 | Reliant Stadium | Recap |
| 6 | September 9 | Kansas City Chiefs | W 20–3 | 3–3 | Reliant Stadium | Recap |
| 7 | September 7 | at Pittsburgh Steelers | L 17–38 | 3–4 | Heinz Field | Recap |
| 8 | September 13 | New York Jets | L 7–24 | 3–5 | Reliant Stadium | Recap |
| 9 | September 12 | Indianapolis Colts | W 34–24 | 4–5 | Reliant Stadium | Recap |
| 10 | September 11 | Indianapolis Colts | W 34–7 | 5–5 | Reliant Stadium | Recap |
| 11 | September 9 | Miami Dolphins | W 30–10 | 6–5 | Reliant Stadium | Recap |
| 12 | September 9 | at San Diego Chargers | W 31–28 | 7–5 | Qualcomm Stadium | Recap |
| 13 | September 7 | Washington Redskins | W 17–6 | 8–5 | NRG Stadium | Recap |
| 14 | September 13 | Kansas City Chiefs | L 20–27 | 8–6 | NRG Stadium | Recap |
| 15 | September 11 | Chicago Bears | W 23–14 | 9–6 | NRG Stadium | Recap |
| 16 | September 10 | Jacksonville Jaguars | L 7–29 | 9–7 | NRG Stadium | Recap |
| 17 | September 9 | at New England Patriots | L 20–27 | 9–8 | Gillette Stadium | Recap |
| 18 | September 9 | at New Orleans Saints | L 28–30 | 9–9 | Mercedes-Benz Superdome | Recap |
| 19 | September 10 | at Kansas City Chiefs | L 20–34 | 9–10 | Arrowhead Stadium | Recap |
| 20 | September 12 | Jacksonville Jaguars | W 37–21 | 10–10 | NRG Stadium | Recap |
Note: Intra-division opponents are in bold text.
Points For: 422 (21.1/g)
Points Against: 425 (21.3/g)