[28] The Mainland Regional High School Mustangs[3] compete in the American Division of the Cape-Atlantic League, an athletic conference comprised of public and private high schools in Atlantic, Cape May, Cumberland and Gloucester counties, operating under the aegis of the New Jersey State Interscholastic Athletic Association (NJSIAA).

[34] The 1973 team won the Group III title against West Essex High School on a tiebreaker following a 0-0 tie after regulation in the championship game.

[38] The team won the 2002 South Jersey Group III state championship, defeating Delsea Regional High School 21-7 in the final.

[39] In 2008, the football team won their first South Jersey Group IV sectional championship with a 21-14 win against Southern Regional High School, going 12-0 for the first time.

[41][42] The boys' basketball team won the 1981 Group III state championship, defeating Randolph High School by a score of 61-47 in the title game.

[46] The boys tennis team won the Group III state championship in 1997, winning the tournament's final against Princeton High School.

[50] The team's average time of 16:19, was a second off of the record set by Christian Brothers Academy in 1982 for the state championship course in Holmdel Township, New Jersey.

[58] In 2018, the boys' lacrosse team won their first Cape-Atlantic League Championship in Mainland's history, beating Ocean City 7-6.

[citation needed] The girls tennis team won the Group III state championship in 1990, defeating Ramapo High School by 4-1 in the tournament final.

[60][61] In 2015, the team won the South Jersey Group II title with a 4-1 win in the tournament final against Seneca High School.

[65] The team won the 2019 Group III title with a 42-35 win against runner-up Chatham High School in the finals of the tournament at the RWJBarnabas Health Arena.

[66] The team advanced to the Tournament of Champions as the sixth seed, falling to Manchester Township High School by a score of 74-44 in the quarterfinal round, to finish the season with a 28-4 record.

The marching band also won the USSBA New Jersey state championship in 2005 and 2006, and were named Northern All-State Group 1A Champions in 2008.

[70] The Mustangs achieved a second undefeated season in 2023 and won the USBands National Championships in 2023 for the first time in school history with a score of 94.40 and winning all major captions in Best Music, Best Visual, and Best Effect.

[72] In 2019, the school won the Looby Cup for the eighth consecutive time, the state title of the New Jersey Drama and Forensic League, which includes competitions in various aspects of theater and speech.

[73] Not only did Mainland come home again with the Looby Cup and first place, several members of the team garnered state champion status in their categories.

In Mainland Regional High School's graduation of 2006, valedictorian Kareem Elnahal gave an unauthorized speech instead of the approved one.

[74][75] During the 2008 graduation ceremony, Salutatorian Jennifer Chau's speech was cut off, after she strayed from her approved text and issued a criticism of the school's administration.

Two girls held responsible were placed on probation and face fines of up to $11,000 to cover costs incurred by police departments from Linwood, Somers Point, Northfield, The State Police, Prosecutors Office, Atlantic City Bomb Squad, Egg Harbor Township K-9 units and Cape May County, who responded to the incidents.

The school was promptly evacuated and 30 students and staff were treated at area hospitals for symptoms related to exposure to the fumes.