The security guard appeared to play a "pivotal role" in keeping the shooting from being worse, police said at a news conference.
Both suspects are believed to be teens and are dead from apparent self-inflicted gunshot wounds, according to police.
A potential motive is being investigated, but police said the shooting is currently being considered a hate crime.
The shooting took place at the largest mosque in San Diego County. The Islamic Center is about 9 miles north of downtown San Diego.
Aerial TV footage showed more than a dozen children holding hands and being walked out of the parking lot of the center that is surrounded by scores of police vehicles. The white mosque is in a neighborhood of homes, apartments and strip malls with Middle Eastern restaurants and markets.
The campus includes the Al Rashid School, which the website says offers courses in Arabic language, Islamic studies and the Quran.
In an Instagram post, the center's director said that "all children and teachers have been evacuated and are safe."
"We have never experienced a tragedy like this before," Taha Hassan, Imam and Director of Islamic Center of San Diego, said at the news conference.
Hassan said he's sending "prayers and standing in solidarity with all the families in our community here, and also the other mosques, and all the places of worship in our beautiful city."
"We strongly condemn this horrifying act of violence," Tazheen Nizam, the executive director of the San Diego chapter of the Council on American-Islamic Relations, said in a statement. "Our thoughts are with everyone impacted by this attack. No one should ever fear for their safety while attending prayers or studying at an elementary school."
Gov. Gavin Newsom's office said he was being briefed.
"We are grateful to the first responders on the scene working to protect the community and urge everyone to follow guidance from local authorities," his office posted on the social platform X.
Police departments in major cities across the country are monitoring the situation.
In Southern California, the Los Angeles Police Department said there's currently no known threat to LA, but the department remains vigilant, "Out of an abundance of caution, we are providing extra patrols at mosques, Islamic centers, and all houses of worship across the City to ensure our communities are safe and feel supported."
In New York City, the NYPD said there's "no known nexus to NYC or specific threats to NYC houses of worship," but the department said it is increasing officer deployments to mosques "out of an abundance of caution."
The Chicago Police Department said in a statement that "while there is no actionable intelligence in Chicago, we are paying special attention to places of worship throughout the city out of an abundance of caution."
The Islamic Center's website says its mission is to not only serve the Muslim population but also "work with the larger community to serve the less fortunate, to educate, and to better our nation." Five daily prayers are held there, and the mosque works with other organizations and people of all faiths on social causes.
ABC News and The Associated Press contributed to this report.