The main objective of this investigation is to study the relationship between compulsive smartphone use and burnout, and the potential mediating effect of negative work-family interaction and loneliness in this relationship. An online questionnaire was applied to a sample of 228 Portuguese workers, from various sectors, aged between 19 and 60 years (mean = 32.32); (standard deviation = 9.25), mostly female (64.5%; n = 154). The data were analyzed through descriptive and inferential statistics. The main results show that the compulsive use of the smartphone is positively and expressively related (beta = 0.258; p < 0.001) to burnout, with compulsive users reporting more symptoms of burnout. In addition, this study shows the mediating power of negative work-family interaction and loneliness, in the relationship between compulsive smartphone use and burnout, with this effect being positive and significant (B = 0.072; 95% CI [0.026; 0.145]; B = 0.068; 95% CI [0.008; 0.141]). These results highlight the need for individuals and organizations to use smartphones with caution, as well as reinforce that companies must develop a way to prevent and treat possible risk factors associated with this phenomenon.