A six-membered heterocyclic compound known as piperazine has two nitrogen atoms within a ring. Numerous studies have shown that piperazine has the potential to be a useful pharmacophore in many harmful pharmacological conditions, such as microbiocidal, anti-inflammatory, anticancer, antioxidant, etc. In this present review, we highlighted the synthetic protocols for piperazine and its analogs and the synthetic protocol for piperazine via rearrangement reactions that have been adopted in recent years. The study also involved a listing of several patents (granted), which comprised important work on piperazine and its derivatives. Among all the methods, the most commonly adopted synthetic methods included the synthesis of piperazine analogs by diaza-cope, hydrolytic, Mumm, Ugi-smiles, [2 + 3] Stevens, Aza-witting, Curtius, Schmidt rearrangement reactions, etc. These synthetic protocols have also been compared based on different reaction conditions, feasibility, and economy to help the researchers in designing their work.