Team BikeExchange's strong roster is built around the Australian, who has shown good early form this season with an impressive performance last week in Paris-Nice.
The 30-year-old feels confident and motivated for the Italian classic.
"I will arrive at Milan-San Remo after a strong week at Paris-Nice," Matthews said.
"We had great work from all the team, and it was really good for me, both physically and also mentally to be back with my GreenEDGE teammates.
“Going to my next challenge of Milan–San Remo, I feel even more motivated to do well and our target is to fight to arrive until the last few metres at the front and play our best chances for victory.
“It will only be my second race of the 2021 season, but I feel good, and we will give our best shot at this unique and special race.”
The 2021 edition of the race has some small tweaks to the course, with the Turchino replaced by the Colle di Giovo, but the climbs are similar (long and rising at shallow gradients) so the dynamic of the race shouldn't change much.
The riders then descend towards the Riviera, re-joining the traditional coastal route in Savona with 112km left to race.
Team BikeExchange's head sport director Matthew White is targeting first place.
“It’s a race that we have had success at in the past," he said.
"We won in our first year as a team in 2012 with Simon Gerrans and then we had a podium finish with Michael Matthews in 2015.
“I believe it’s a race that Michael can win, and I think going into the race, he showed us that he has good form in Paris-Nice and we are certainly aiming to win “SanRemo” on Saturday.
"We have a really strong and dedicated team to look after Michael."