BackgroundBuilding on the job demands–resources (JD–R) model and regulatory focus theory, this study examined how regulatory foci shaped the effects of different job demands and resources on both negative and positive workplace outcomes among medical staff.MethodsTwo independent studies (NStudy 1 = 267; NStudy 2 = 350) were designed for cross-validation. Participants completed a battery of measures evaluating job demands (workload, emotional demands, interpersonal stress), job resources (psychological safety, perceived organizational support, servant leadership), and well-being (job burnout, affective commitment, job satisfaction).ResultsMultiple linear regression analyses showed employees’ well-being was affected by job demands and resources through energetic and motivational processes, respectively. The deleterious effect of emotional demands on job burnout was pronounced in individuals with weak prevention focus (B = 0.392, standard error [SE] = 0.069, p < .001). Psychological safety (Study 1) and servant leadership (Study 2) had stronger positive associations with motivational outcomes among individuals with weak promotion focus than those with strong promotion focus (B = 0.394, SE = 0.069, p < .001; B = 0.679, SE = 0.121, p < .001; and B = 0.476, SE = 0.072, p < .001, respectively).ConclusionWe used two samples to examine and cross-validate the joint effects of job characteristics and personal traits on workplace well-being among Chinese medical staff. Although heterogenous, the results showed regulatory foci were especially important in determining the effects of job demands and resources on well-being when there was (autonomous) self-regulation in the workplace.