To start the season, the Lions traveled south to Tampa, Florida to take on the Tampa Bay Buccaneers. The Lions scored first in the first quarter with a 23 yard field goal by Jason Hanson. The Buccaneers tied it up with a 38 yard field goal by Connor Barth, then took the lead when Aqib Talib intercepted a pass from Matthew Stafford and ran it in 28 yards. The Lions responded with a 28 yard field goal. In the second quarter, Detroit took the lead with a 36 yard touchdown catch by Calvin Johnson, and later added more points when Tony Scheffler caught a 11 yard pass. Tampa Bay responded with a 31 yard field goal just before halftime. The second half was relatively quiet, with each team only scoring 1 touchdown. First Detroit's Calvin Johnson caught a 1 yard pass in the third quarter. The game's final points came when Mike Williams of Tampa Bay caught a 5 yard pass.  With the win, the Lions went 1–0 for the first time since 2007.
For their home opener, the Lions hosted the Kansas City Chiefs. The Lions scored first when Calvin Johnson caught a 15 yard pass for a touchdown. Kansas City then scored their only points of the game with a 33 yard field goal by Ryan Succop. In the second quarter, the Lions' Tony Scheffler caught a 36 yard pass for a touchdown. They added to their lead with two field goals from Jason Hanson, from 51 and 28 yards respectively. After halftime, the Lions scored 4 consecutive touchdowns: first a 1 yard catch by Calvin Johnson, then in the fourth quarter a 9 yard catch by Jahvid Best. Best then scored again on a 1 yard run. The Lions capped their victory with a 1 yard run by Keiland Williams.  The blowout win set the franchise record for largest margin of victory. It was the first time the Lions went 2–0 since 2007. Lions QB Matthew Stafford - who completed 23 of 39 passes, threw for 294 yards and 4 touchdowns - won the FedEx Air NFL Player of the Week for his performance. 
In week 3, the Lions traveled west to Minneapolis, Minnesota to face their NFC North Division rivals the Minnesota Vikings. The first half was all Minnesota. In the first quarter, the Vikings' Ryan Longwell made 2 consecutive field goals, from 33 and 41 yards out respectively. In the second quarter came 2 consecutive Minnesota touchdowns. First on a 6 yard run by Adrian Peterson, then an 8 yard catch by Visanthe Shiancoe. After halftime, the Lions mounted a comeback. In the third quarter, Detroit's Calvin Johnson caught a 32 yard pass for a touchdown. They added more points with a 28 yard field goal by Jason Hanson. In the fourth quarter, Calvin Johnson caught another touchdown pass, this one from 5 yards out. Detroit then tied it up with a 50 yard field goal, and took their first lead of the game with a 40 yard Jason Hanson 3-pointer. Minnesota tied it up again with a 49 yard field goal late in the game, taking it to overtime. Detroit won the coin toss and got the ball first, then scored a 32 yard field goal to win the game.  Detroit's 20-point comeback was biggest on the road in team history. It was also the first time the Lions beat the Vikings at the Metrodome since 1997. It is also the first time Lions went 3-0 since 1980.
In week 4, the Lions traveled south to Arlington, Texas to take on the Dallas Cowboys. The Cowboys dominated for the first half. First came a 25 yard touchdown catch by Dez Bryant. In the second quarter, Bryant scored more points with a 6 yard touchdown catch. Dallas added more points with a 41 yard field goal by Dan Bailey. The Lions then got their only points of the first half with a 33 yard field goal by Jason Hanson. The Cowboys responded with a 35 yard field goal just before halftime. After the break, Dallas added more points with a 1 yard touchdown catch by Jason Witten. The Lions responded with 2 consecutive defensive touchdowns: first a 34 yard interception return by Bobby Carpenter, then a 56 yard pick 6 by Chris Houston. The Cowboys scored their final points of the game with a 23 yard field goal late in the third quarter. In the fourth quarter, the Lions continued their comeback with a 23 yard touchdown catch by Calvin Johnson. They made it a three point game with a 51 yard field goal by Jason Hanson, and took their first lead of the game late in the final quarter when Calvin Johnson caught his second touchdown of the game, from 2 yards out to become only the 2nd player in NFL history to record at least 2 touchdown catches in 4 straight games. The other to do so is former Vikings receiver Chris Carter. The Lions defense held off Dallas for the win.  Like the previous week, the Lions came back and won it in the final moments of the game after being down by a large margin at halftime. This was also the largest comeback the Dallas Cowboys have ever allowed, and it is the largest comeback by a road team in NFL history as the Cowboys were up by 24 in the 3rd quarter with the score 27–3. It is the first time Lions are 4–0 since 1980. This also was its franchise-record fifth straight road win. Ironically, their last game at Dallas was the franchise record 26th straight road loss.
In week 5, the Lions hosted a nationally televised primetime NFC North Division duel against the Chicago Bears. It was the first ever Monday Night Football game at Ford Field, the first MNF appearance for the Lions since 2001, and the first Monday night game in the city of Detroit since 1974. Neither team scored in the first quarter. In the second quarter, the Lions got an early lead with a 73 yard catch and run by Calvin Johnson and with this Calvin Johnson became the first receiver in NFL history to record 9 touchdown catches in 5 games. The Bears got on the board with a 44 yard field goal by Robbie Gould, and took the lead with a 9 yard catch by Kellen Davis. After halftime, the Lions regained the lead and never gave it back. First came an 18 yard TD catch by Brandon Pettigrew. A few minutes later, Detroit's Jahvid Best ran in a TD from 88 yards out, the second longest touchdown run in franchise history. Each team scored a field goal in the fourth quarter. First Chicago from 49 yards out. The Lions sealed their victory with a 31 yard 3 pointer.  Counting the end of the 2010 season, the Lions have now won 9 consecutive games, which is the NFL's longest active regular season winning streak. With the win, the Lions started 5–0 for the first time since 1956.