The piperazine scaffold is a privileged structure frequently found in biologically active compounds. Piperazine nucleus is found in many marketed drugs in the realm of antidepressants (amoxapine), antipsychotics (bifeprunox), antihistamines (cyclizine and oxatomide), antifungals (itraconazole), antibiotics (ciprofloxacin), etc. This is one of the reasons why piperazine based compounds are gaining prominence in today's research. In addition to the ring carbons, substitution in the nitrogen atom of piperazine not only creates potential drug molecules but also makes it unique with versatile binding possibilities with metal ions. Piperazine ring-based compounds find their application in biological systems with antihistamine, anticancer, antimicrobial and antioxidant properties. They have also been successfully used in the field of catalysis and metal organic frameworks (MOFs). The present review focuses on the synthesis and application of different piperazine derivatives and their metal complexes having diverse applications.