Previous research on the association between job characteristics and employee well-being has returned mixed results. In particular, the possible impact of individual appraisal of these job characteristics has not been well-acknowledged. To address this limitation, we drew on appraisal theory and examined (a) how workers appraise particular job characteristics, and (b) how these appraisals affect the relationships between these job characteristics and well-being (i.e., work engagement and burnout). We tested our hypotheses across two studies. In a cross-occupation survey (Study 1, n = 514), we found that job characteristics of “demands” (time urgency, role conflict, and emotional demands) and “resources” (autonomy, supervisor and colleague support, and feedback) can to some degree be appraised as both challenges and hindrances. In addition, moderation analysis showed that challenge appraisal can mitigate the negative impact of job demands on burnout. Interestingly, the beneficial effects of job resources on employee well-being (i.e., increasing engagement, and decreasing burnout) were weaker if workers appraised a certain resource as hindering. In Study 2 (n = 316 nurses in a hospital), the results generally supported our predictions again. These findings on the effects of appraisal contribute by broadening the theory on job characteristics-outcomes relationships.