Context <p>Spirooxindoles represent a distinguished category in medicinal chemistry. Their three-dimensional structure enhances interactions with many biological targets. They exhibit anticancer, antibacterial, antiviral, anti-inflammatory, antioxidant, and antidiabetic properties. Various methods were applied to synthesize spirooxindoles and their derivatives. This review focuses on different synthetic approaches, pharmacological activities, and molecular insights of spirooxindoles that have been published in the first quarter of the twenty-first century. Furthermore, research gaps were highlighted, such as the lack of in vivo validation, toxicity profiling, and standardized yield/replicability data. Twelve synthesis procedures were statistically compared. A total of 40 studies were pharmacologically summarized, and their molecular insights were highlighted.</p> Methods <p>The method of literature search engines and citation databases such as Google Scholar, PubMed, Web of Science, and Scopus was utilized for the present review and searching for specific research questions. Then each of the transformed queries has been processed by running the applied inclusion &amp; exclusion criteria in order to retrieve a focused set of candidate papers, and 219 papers were retrieved. Out of the total retrieved papers, 99 of them were mostly relevant.</p> Graphical abstract <p></p>