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 (β = 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.