Incumbent Democratic governor Lou Leon Guerrero, who was elected in 2018 with 50.7% of the vote, sought a second term.

San Nicolas' campaign emphasized improving staffing at the Guam Behavioral and Wellness Center in order to better respond to drug addiction and mental health issues on the island.

San Nicolas criticized Leon Guerrero's record on land return for Chamorro communities, and alleged insufficient transparency regarding the Simon Sanchez High School rehabilitation project.

[6] During the general election, Democratic primary runners-up San Nicolas and his running mate, Salas Matanane, publicly urged Guamanians to vote against Leon Guerrero's reelection.

[11] Republican nominee Camacho criticized the governor for allegedly "hoarding" around $300 million in federal relief funds in the Bank of Guam, of which Leon Guerrero had previously been CEO of.