Week 6 one loss NFL team parlay: This DraftKings parlay involving Colts, Buccaneers, 49ers, Lions pays 5-1

The Indianapolis Colts (4-1) and the Arizona Cardinals (2-3) link up at 1 p.m. ET. Last week, Indianapolis blew out the Las Vegas Raiders 40-7. Meanwhile, the Cardinals fell 22-21 to the Tennessee Titans in Week 5. According to the latest Week 6 NFL odds, the Colts are a 7.5-point favorite and the Over/Under is 46.5. Meanwhile, the San Francisco 49ers (4-1) are traveling to play the Tampa Bay Buccaneers (4-1) without quarterback Brock Purdy (toe) at 4:25 p.m. ET. In addition, the Kansas City Chiefs (2-3) and Detroit Lions (4-1) collide at 8:20 p.m. ET on Sunday Night Football. Three NFL picks, including the Colts, Buccaneers, 49ers, and Lions, are part of a one-loss NFL parlay at DraftKings Sportsbook that pays out over 5-1.

The model, which simulates every NFL game 10,000 times, is up well over $7,000 for $100 players on top-rated NFL picks since its inception. The model is on a sizzling 41-21 run on top-rated picks dating back to 2024. Anybody following its NFL betting picks at sportsbooks and on betting sites could have seen strong returns.

Three betting picks for NFL Week 6 (odds subject to change): 

• Cardinals vs. Colts (-7) (-112)
• 49ers vs. Buccaneers: Over 47.5 total points (-110)
• Lions (+2.5) vs. Chiefs (-110)

Combining the model's three picks into an NFL parlay at DraftKings would result in a payout of +589 (risk $100 to win $589).

Cardinals vs. Colts (-7.5) (-112, DraftKings)

Colts quarterback Daniel Jones ranks third in the NFL in passing yards (1,290), first in QBR (79.7), and has six passing touchdowns. They are ninth in the league in rushing offense (128.2), led by Jonathan Taylor, who leads the NFL in rushing yards (480) and rushing touchdowns (6). Cardinals Kyler Murray is dealing with a foot injury, which caused him to miss practice. Indianapolis is 3-0 ATS as the home team in 2025. SportsLine's model predicts that the Colts will cover the spread in 55% of simulations. 

49ers vs. Buccaneers: Over 47.5 total points (-110, DraftKings)

San Francisco is fifth in total offense (375.8) and first in passing offense (290.6). They are averaging 21.2 points but have scored 25-plus points twice this season. 49ers running back Christian McCaffrey leads the team in rushing yards (282) and receiving yards (387) with three receiving scores. Meanwhile, Tampa Bay is seventh in scoring offense (27). Tampa Bay quarterback Baker Mayfield is fourth in passing yards (1,283) and tied for third in passing touchdowns (10). SportsLine's model predicts these teams combine for 50 total points and has the over cashing in 53% of simulations. 

Lions (+2.5) vs. Chiefs (-110, DraftKings)

The Lions have won four straight games, scoring 34-plus points in every game. Detroit is sixth in the NFL in total offense (365) and first in scoring offense (34.8). Quarterback Jared Goff ranks 10th in passing offense (1,187) and first in passing touchdowns (10). The Lions are 3-0 ATS after a win and 4-1 ATS in all games this season. Meanwhile, the Chiefs are 1-2 as the favorite this season. In the last outing at Arrowhead between these teams, Detroit came out with a 21-20 victory. SportsLine's model has the Lions covering the spread in 54% of simulations.