Over the last four decades, a number of γ-spirocyclic butenolide containing natural products, drugs, and medicinally useful synthetic compounds have been reported. In this review, we discuss diverse chemical approaches to synthesize γ-spiro butenolides and their application towards natural product synthesis. The collective perception of various methods may allow superior approaches capable of delivering efficient synthetic approaches to obtain γ-spiro butenolide comprising natural products and their hybrid analogues for further drug discovery and development.