Background Leprosy is potentially debilitating. The risk factors related to physical disabilities associated with leprosy disease in Yunnan, China was not clear. Methodology/Principal findings We studied 10644 newly detected leprosy patients from Yunnan, China, from 1990 to 2019. Factors associated with Grade 1 (G1D) and Grade 2 (G2D) physical disabilities or overall physical disabilities (combined G1D and G2D) associated with leprosy were analyzed using multinomial and ordinal logistic regression analyses. The following factors were associated with the development of physical disability in these patients with leprosy: delayed diagnosis [odds ratio (OR): 5.652, 4.399, and 2.275; 95% confidence intervals (CIs): 4.516-7.073, 3.714-5.212, and 2.063-2.509; for >= 10, 5-10 y, and 2-5 years, respectively], nerve damage (OR: 3.474 and 2.428; 95% CI: 2.843-4.244, and 1.959-3.008; for 2 and 1 damaged nerves, respectively), WHO classification of PB (OR: 1.759; 95% CI: 1.341-2.307), Ridley-Jopling classification (OR: 1.479, 1.438, 1.522 and 1.239; 95% CI: 1.052-2.079, 1.075-1.923, 1.261-1.838, and 1.072-1.431; for TT, BT, BB, and BL when compared with LL, respectively), advanced age (OR: 1.472 and 2.053; 95% CI: 1.106-1.960 and 1.498-2.814; for 15-59 and over 60 years old, respectively), zero skin lesions (OR: 1.916; 95% CI: 1.522-2.413), leprosy reaction (OR: 1.528; 95% CI: 1.195-1.952), rural occupation (OR: 1.364; 95% CI: 1.128-1.650), Han ethnicity (OR: 1.268; 95% CI: 1.159-1.386), and male sex (OR: 1.128; 95% CI: 1.024-1.243). Conclusions Delayed diagnosis, nerve damage, no skin lesions, WHO and Ridley-Jopling classifications, leprosy reactions, advanced age, rural occupation, Han ethnicity, and male sex were associated with disability in leprosy patients. Identifying risk factors could help to prevent physical disability. Author summary Leprosy, caused by Mycobacterium leprae (M. leprae), is a potentially disabling infectious disease. After achieving the national elimination target, the focus of leprosy care is now shifting from implementing multidrug therapy (MDT) to accelerating the reduction in disease burden, especially stopping leprosy and its complications, with targets for 2020 of 0 new child cases with Grade 2 disability (G2D) and <1 per million population new leprosy cases with G2D. We assessed physical disabilities and deformities of newly detected leprosy patients in Yunnan, an endemic area of leprosy disease in China, from 1990-2019 and the clinical and demographic factors associated with physical disabilities and deformities. We found that delayed diagnosis, nerve damage, WHO and Ridley-Jopling classifications, lack of skin lesions, leprosy reactions, advanced age, rural occupation, Han ethnicity, and male sex were risk factors for physical disabilities in patients with leprosy disease. The findings are important because physical disability is the main sequelae of leprosy disease that leads to stigma, discrimination, and socioeconomic burden. Understanding the related risk factors would be helpful for preventing the physical disability associated with leprosy disease.