Purpose: The aim of this study is to investigate the associations between patient activation and total costs in cancer patients treated with total laryngectomy (TL). Methods: All members of the Dutch Patients’ Association for Laryngectomees were asked to participate in this cross-sectional study. TL patients who wanted to participate were asked to complete a survey. Costs were measured using the medical consumption and productivity cost questionnaire and patient activation using the Patient Activation Measure (PAM). Sociodemographic and clinical characteristics were self-reported, and health status measured using the EQ-5D. The difference in total costs from a healthcare and societal perspective among four groups with different PAM levels were compared using (multiple) regression analyses (5000 bootstrap replications). Results: In total, 248 TL patients participated. Patients with a higher (better) PAM (levels 2, 3, and 4) had a probability of 70, 80, and 93% that total costs from a healthcare perspective were lower than in patients with the lowest PAM level (difference €−375 to €−936). From a societal perspective, this was 73, 87, and 82% (difference €−468 to €−719). After adjustment for time since TL, education, and sex, the probability that total costs were lower in patients with a higher PAM level compared to patients with the lowest PAM level changed to 62–91% (healthcare) and 63–92% (societal). After additional adjustment for health status, the probability to be less costly changed to 35–71% (healthcare) and 31–48% (societal). Conclusions: A better patient activation is likely to be associated with lower total costs from a healthcare and societal perspective.