The 2022 mpox epidemic was characterized by rapid, underdetected local spread among high-risk groups following initial regional viral seeding events. Local behavioral changes played a larger role in curbing transmission than did travel restrictions and vaccination campaigns. Phylodynamic models revealed swift early mpox spread between five global regions, with extensive, underdetected dissemination promoting rapid local transmission. Later mpox introductions had a negligible role in prolonging regional epidemics. The North American epidemic declined before 10% of high-risk individuals had vaccine-induced immunity, highlighting the importance of broader routine specimen screening for emerging infectious diseases and the integration of genomic and epidemiological information for early outbreak control. The study emphasizes the need for rapid pathogen detection and public health responses to protect vulnerable populations from mpox and other emerging infections.The 2022 mpox epidemic was characterized by rapid, underdetected local spread among high-risk groups following initial regional viral seeding events. Local behavioral changes played a larger role in curbing transmission than did travel restrictions and vaccination campaigns. Phylodynamic models revealed swift early mpox spread between five global regions, with extensive, underdetected dissemination promoting rapid local transmission. Later mpox introductions had a negligible role in prolonging regional epidemics. The North American epidemic declined before 10% of high-risk individuals had vaccine-induced immunity, highlighting the importance of broader routine specimen screening for emerging infectious diseases and the integration of genomic and epidemiological information for early outbreak control. The study emphasizes the need for rapid pathogen detection and public health responses to protect vulnerable populations from mpox and other emerging infections.