Activity-based workplaces (ABWs) are implemented with possible implications for health, well-being, and work satisfaction in the workplace. Drawing on the theoretical framework, i.e., sense of coherence (SOC), the aim was to investigate how indicators pf SOC—meaningfulness, manageability and comprehensibility—are associated with, or function as barriers or facilitators for, health, well-being and work satisfaction during relocation to an ABW. We followed the implementation of ABWs at the Swedish Transport Administration (2018–2019). Questionnaires were administered before (n = 536), 3 months (n = 409) and 9 months (n = 373) after relocation. Focus group interviews (15) were conducted before and after. Data were analyzed using repeated measures ANOVA and content analysis. Relocation to an ABW was associated with a reduced work satisfaction (physical p < 0.001; psychosocial p < 0.001), and minor changes in health and occupational well-being during relocation (p > 0.001). The reduction in work satisfaction was smaller among employees with high meaningfulness in the relocation process (p < 0.001). All SOC indicators were positively associated with overall health, well-being and work satisfaction (p < 0.001). Interviews suggested that meaningfulness was facilitated by participation in the presented activities and that communication before relocation was crucial. The results indicate that organizations implementing ABWs should promote perceived meaningfulness in the process to mitigate possible declines in satisfaction with the physical and psychosocial work environment.