A group of tricyclic phenothiazine (6a, 6b, 7a–l) and phenoselenazines (12a, 12b, 13a–l) were designed, synthesized and evaluated as multi-targeting ligands aimed at the cholinergic, amyloid and oxidative stress pathways of Alzheimer's disease. The phenothiazine derivative 7j (2-chloro-10H-phenothiazin-10-yl-(4-methoxyphenyl)methanone), was identified as the best dual, nonselective cholinesterase inhibitor (AChE IC50 = 5.9 ± 0.6 µM; BuChE IC50 = 5.3 ± 0.5 µM), whereas in the corresponding phenoselenazine series, 13j (2-chloro-10H-phenoselenazin-10-yl- (4-methoxyphenyl)methanone) exhibited good nonselective cholinesterase inhibition (AChE IC50 = 5.8 ± 0.4 µM; BuChE IC50 = 4.9 ± 0.5 µM). Interestingly, N-10 unsubstituted phenothiazine 6a (AChE IC50 = 7.3 ± 0.6 µM; BuChE IC50 = 5.8 ± 0.5 µM; Aβ1-42 aggregation inhibition = 62%; DPPH scavenging = 92%), and the corresponding phenoselenazine bioisotere 12a (AChE IC50 = 5.6 ± 0.4 µM; BuChE IC50 = 3.0 ± 0.5 µM; Aβ1-42 aggregation inhibition = 45.6%; DPPH scavenging = 84.4%), were able to exhibit multi-targeting ability by demonstrating cholinesterase inhibition, beta-amyloid aggregation and antioxidant properties. These results show that fused tricyclic ring systems based on either a phenothiazine or phenoselenazine templates can be useful to develop hybrid small molecules to target multiple pathological routes associated with Alzheimer's disease.