Objective To investigate the association of sociodemographic factors, lifestyle, work organization, and professional profile with work ability in professional drivers. Methods Cross-sectional study with 449 drivers in Curitiba, Paraná (Brazil). Participants were assessed regarding their work ability (Work Ability Index; WAI), sociodemographic, lifestyle (physical activity [Baecke’s questionnaire] and stress [Work Stress Scale]), work organization, and professional profile using self-completion instruments. The association of WAI with sociodemographic factors, lifestyle, work organization, and professional profile was determined by multivariable ordinal logistic regression models. Results Lifestyle factors best explained the WAI variability. The WAI was inversely associated with stress and occupational physical activities but directly associated with leisure activities and locomotion and leisure-time physical exercise. Conclusions Our data also challenges the concept that sociodemographic information and ergonomics organization influence determining the work ability of this population.