Modern medicinal chemistry has come to its bottleneck and is full of challenges, specially when facing with long-term central nervous system (CNS) disorders induced by several factors, such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). In order to probe these challenges, multi-target directed ligands (MTDLs) design has been applied recently by medicinal scientists trying to get single compounds that can simultaneously modulate multiple targets. In addition, natural products have drawn the attention of drug developers again in recent years, as they have been used by human race for thousands of years and are full of diversity with their concomitant high potential to exhibit biological activities. We hereby review some of the research within the last few years focusing on multiple-target compounds acting in the CNS using natural products as lead resources. The target compounds obtained and described here represent bioactive hybrids either covalently connected or obtained by fusion of different bioactive moieties with at least one part derived from or representing directly natural products, along with some natural compounds themselves showing multiple pharmacological activities. We describe suitable ways to connect the drug components chemically, how to use the approach to enhance biological activity and selectivity, as well as potential drawbacks of the hybrid approach. This review will also show the rationale that these MTDLs are more than just the sum of their components but in many cases should be considered as new pharmacological entities in their own respect.