<p>Human brucellosis has expanded continuously in Yunnan Province, China; however, its epidemiological dynamic remains unclear. In the present study, we used joinpoint regression and space–time cluster analyses to illustrate the epidemic profile of human brucellosis in Yunnan. From 2006 to 2024, a total of 7360 cases were reported; the incidence rate increased from 0.002/100,000 (<i>n</i> = 1) in 2006 to 4.526/100,000 (<i>n</i> = 2,124) in 2024. Human brucellosis exhibited two upward stages: a significantly increasing stage from 2006 to 2014 (annual percent change [APC]=76.04, <i>p</i> &lt; 0.05) and another continuously rising stage from 2014 to 2024 (APC = 30.24). With 69.47% of cases (5,113/7,360) in male individuals and 30.53% in (2,247/7,360) female ones. Among the total, 83.72% (6,162/7,360) of cases were reported in farmers and fell into the age group 45–59 years (41.14%, 3028/7,360). Most cases were reported from May to August, and the disease showed a significant seasonal trend. Human brucellosis in all 16 cities of the province exhibited a significantly increasing trend; the range of average APC in the 16 cities was from 63.36 (<i>p</i> &lt; 0.05) in Kunming to 162.75 in Yuxi (<i>p</i> &lt; 0.05). The number of reported cases expanded from one county in 2006 to 101 counties in 2024. In 2024, the incidence in 53 counties was greater than 2.00/100,000, indicating that human brucellosis has become an endemic disease in Yunnan Province. Spatiotemporal scan analysis identified two high-rate clusters (designated I and II), with High-High cluster counties exhibiting a continuous east-to-west expansion across Yunnan. The rapid geographic expansion of human brucellosis in Yunnan, China necessitates the urgent development and implementation of tailored countermeasures to curb its spread.</p>