The extraction of total lipids and tocopherol compounds from Patagonian squid () by-products (viscera, heads, skin, etc.), resulting from squid mantel commercialisation, was studied. An optimisation simplex-lattice design by employing low-toxicity solvents (ethanol, acetone, and ethyl acetate) was carried out taking into account their relative concentrations. The variance analysis of data showed that the quadratic model was statistically significant ( < 0.05); empirical coded equations were obtained as a function of the low-toxicity solvent ratios. The optimised lipid extraction was obtained by employing the 0.642/0.318/0.040 (ethanol/acetone/ethyl acetate) solvent ratio, respectively, leading to an 84% recovery of the total lipids extracted by the traditional procedure. In all extracting systems tested, the presence of α-, γ-, and δ-tocopherol compounds was detected, α-tocopherol being the most abundant. For α-, γ-, and δ-tocopherol compounds, the optimisation process showed that acetone extraction led to the highest concentrations in the lipid extract obtained (2736.5, 36.8, and 2.8 mg·kg lipids, respectively). Taking into account the recovery yield on a by-product basis, the values obtained for the three tocopherols were included in the 88.0-97.7%, 80.0-95.0%, and 25-75% ranges, respectively, when compared to the traditional extraction. This study provides a novel and valuable possibility for α-tocopherol extraction from marine by-products.