Techniques for extracting important bioactive molecules from seafood byproducts, viz., bones, heads, skin, frames, fins, shells, guts, and viscera, are receiving emphasis due to the need for better valorization. Employing green extraction technologies for efficient and quality production of these bioactive molecules is also strictly required. Hence, understanding the extraction process parameters to effectively design an applicable optimization strategy could enable these improvements. In this review, statistical optimization strategies applied for the extraction process parameters of obtaining bioactive molecules from seafood byproducts are focused upon. The type of experimental designs and techniques applied to criticize and validate the effects of independent variables on the extraction output are addressed. Dominant parameters studied were the enzyme/substrate ratio, pH, time, temperature, and power of extraction instruments. The yield of bioactive compounds, including long-chain polyunsaturated fatty acids, amino acids, peptides, enzymes, gelatine, collagen, chitin, vitamins, polyphenolic constituents, carotenoids, etc., were the most studied responses. Efficiency and/or economic and quality considerations and their selected optimization strategies that favor the production of potential bioactive molecules were also reviewed.