This study aimed to investigate diabetes distress, happiness, and its associated factors of patients with type 2 diabetes mellitus (T2DM) treated by different therapies, and to analyze the related impact factors. A total of 1512 patients with T2DM were randomly selected from 18 tertiary hospitals in Hunan province from January 2016 to April 2016 who has been treated with oral antidiabetics monotherapy, insulin monotherapy, and combination therapy. Use the general information questionnaire, WHO-5 (the World Health Organization 5 well-being index) and PAID (the problem areas in diabetes scale) to collect the data. There are 846 (55.95%) patients that have serious emotional disorders, and the diabetes related distress in insulin treatment group was higher than that in combination treatment group (P < .05). Happiness of T2DM patients in combination therapy was higher than oral antidiabetic drug monotherapy and insulin monotherapy (P < .05). There was a negative correlation between diabetic suffering and happiness in patients with different treatments (R ranged from -0.335 to -0.436, P < .001). Age and happiness experience could explain 14.8% of the variance. Acute and chronic complications, controlled blood glucose level, lifestyle, therapies, and school education can explain 18.3% variance. Under different therapies, the suffering and happiness of T2DM patients differed from each other. The suffering and happiness of T2DM were related to different therapies, age, complications, glycaemic control, lifestyle, school education, and so on.