Approximately one in five adolescents experience mental health problems globally. However, studies on mental health problems in Chinese high school students are few. Therefore, this study examined the status and associated factors of mental health problems in high school students in China. A stratified two-stage cluster sampling procedure was adopted, leading to a final sample of 15,055 participants from 46 high schools in all 17 provincial cities of Henan province, China. Self-reported questionnaires were used to collect the data. A mental health problems variable was assessed using the Mental Health Inventory of Middle School Students. The positive rate of mental health problems among high school students was 41.8%, with a male predominance (43.3% versus 40.2% in females; p < 0.01). The most frequent mental health problem was academic stress (58.9%). Higher grades, physical disease, chronic constipation, alcohol consumption, engagement in sexual behavior, residence on campus, and living in nonurban areas and with single-parent families were significantly associated with higher odds of having mental health problems (p < 0.05). We suggest that the prevention of mental health problems in high school students be strengthened, especially in students with physical illnesses, unhealthy behaviors, and single-parent families.