The Indians actually led 10-0 with five minutes to go in the first half but the Panthers struck for 24 points before halftime.
Northwest got a 37-yard field goal from Chris Oaks and then quarterback Mike Sarnese, who went 16-for-41 for 205 yards, threw the first of his three touchdown strikes to Pete Bourdon from five yards out.
E.O. Smith scored on a 55-yard touchdown pass, a safety, a 40-yard touchdown pass and a 70-yard run for the 24-10 lead at halftime.
The Indians hung tough but big plays spelled the difference.
"We played well in the first half but then gave up three big plays that really hurt us," Northwest coach Mike Tyler said. "That has been the story the first two games. We have been giving up way too many big plays. We had been doing a great job up until that point."
Tyler liked the fight in his team in the second half.
"In the second half we hung right in there with them," he said. "We were don two scores going into the fourth quarter but then things kind of fell apart for us as they did the first game against East Catholic. We kind of got worn down and made some mistakes on defense.
"Let's not lose sight of the fact that E.O. Smith has a great football team this year just as they did last year. East Catholic is also a very strong team so we played two great teams to start the season.
"I'm proud of the way the kids hung in the game and we played well for much of the game. Our tackling is not very good right now but we are going to continue to work on it and try to improve. I think the team has been working hard and will continue to work hard and I'm looking forward to the improvement. We are looking to get better from week to week."
Northwest plays at 1-0-1 Vinal Tech/Coginchaug at 4 p.m. at Palmer Field in Middletown Friday night.
