Born in Weymouth, Massachusetts to Robert and Melissa Mewis, Samantha grew up in Hanson, Massachusetts where she attended Whitman-Hanson Regional High School and played on the soccer team, tallying 77 goals and 34 assists during her time there. She grew up with her older sister Kristie, playing soccer for numerous youth teams, including club team, Scorpions SC, as well as the under-17 and under-20 United States national teams. Mewis earned Parade All-American honors twice during her high school years and was named the National Soccer Coaches Association of America national player of the year in 2010. In 2011, she was named Gatorade Massachusetts Girls Soccer Player of the Year for the second time after receiving the accolade previously for 2009–10. The same year, she was named ESPN RISE All-American after scoring 30 goals and serving 8 assists during her senior year.
In her freshman year, Mewis was second on the team in scoring with six goals and seven assists, only bested by current United States women's national soccer team member Sydney Leroux and was named to the Pac-12 All-Freshman Team. Due to national team commitments, Sam missed the first six games of her sophomore season, but finished the year with 3 goals and 3 assists in 16 games. In her junior year, Mewis helped UCLA win the Pac-12 championship on the way to its first NCAA Championship. In December 2014, she was named the winner of the 2015 Honda Award for soccer by the Collegiate Women Sports Awards (CWSA).
In 2013, Mewis signed with the Pali Blues in the W-League. The team won the western conference title as well as the national championship in July 2013.
Mewis was selected fourth overall by the Western New York Flash in the 2015 National Women's Soccer League entry draft. She started all 20 regular-season games for the Flash, scoring 4 goals and providing 4 assists to share the top of the team scoring leaderboard with Lynn Williams. On September 9, 2015, the NWSL announced that Mewis was selected as a finalist for the NWSL Rookie of the Year Award for the 2015 season, along with Sofia Huerta and the eventual winner, Danielle Colaprico.
It was announced on January 9, 2017, that the Western New York Flash was officially sold to new ownership, moved to North Carolina, and rebranded as the North Carolina Courage.
Mewis was a member of the United States under-17 team that was runner-up at the 2008 FIFA U-17 Women's World Cup in New Zealand. As her sister Kristie was also a member of the team, they were the first sisters to represent the United States at a Women's World Cup. They also played together at the 2010 FIFA U-20 Women's World Cup. At the 2012 FIFA U-20 Women's World Cup, Mewis helped the team win the championship after defeating Germany 1–0 in the final.
On January 24, 2014, Mewis was named for the first time to the senior national team roster for friendlies against Canada and Russia. She made her debut for the team at the 2014 Algarve Cup during the team's second match of the tournament and 1–0 loss to Sweden.
After a spell out of the team, Mewis was invited back to the senior team following their success at the 2015 FIFA Women's World Cup. She continued to get regular playing time, scoring four goals in 2016 including the winning goal against Germany in the 2016 She Believes Cup that won the United States the trophy.
Mewis' sister, Kristie, plays for the United States women's national soccer team and professionally for the Houston Dash.