Objectives: To analyze the effect of a comprehensive program of cognitive stimulation with digital inclusion, physical activity and social interaction, called "Oficina da Lembrança" (OL), on the cognitive status and concentration of biomarkers of neuroplasticity, neurodegeneration in adults aged 50 years and over attending a Memory Clinic. Methods: In this pilot randomized controlled study, 64 patients without dementia aged 45 to 79 years, seen at a University Memory Clinic in Southern Brazil, were randomly allocated to the intervention and control groups. The intervention consisted of participation in OL for 12 weeks. Serum biomarkers (brain-derived neurotrophic factor [BDNF], S100β, and neuron-specific enolase [NSE]) and cognitive status were analyzed as primary and secondary outcomes. The Wilcoxon test and Generalized Estimating Equations (GEE) were applied. Results: Of the 64 patients invited to participate in the study, 33 (intervention: 17, control: 16) completed the study with all data. Improvement of cognitive status was significant in the intervention group (22.6 to 24.5) but not in the control group (20.1 to 21.1). There was a significant reduction of BDNF in OL participants, but no significant change was observed in the neurodegenerative biomarkers S100β or NSE. The concentration of BDNF decreased significantly post-OL in the intervention group (-288.1, 95%CI −362.1 to −94.1), even after adjusting for sex, age, and educational level. Cognitive status was significantly improved in OL participants. Conclusion: The OL program improved cognitive status, reduced serum BDNF levels, and empowered digitally excluded older adults. There was no effect of this intervention on S100β or NSE. Clinical trial registration: This study has a Universal Trial Number (UTN) U1111-1195-2642 and was registered in the Brazilian Clinical Trials Registry (ReBEC), number RBR-38X665.