SummaryExtracting conditions of lipid compounds (phospholipids, PLs, and ω3 fatty acids, FAs) from Patagonian squid (Doriteuthis gahi) waste were optimised by employment of a Simplex‐Lattice design. For it, different concentrations of low‐toxicity solvents (ethanol, acetone and ethyl acetate; single and binary and ternary mixtures) were tested. As a result, the multiple regression ANOVA proved that the quadratic model was significant (p<0.05) for PL and eicosapentaenoic acid (EPA) contents and for total polyunsaturated/total saturated and total ω3/total ω6 FA ratios. Thus, the ANOVA application of the fitting model led to the following optimised values for such parameters: 477.42 g·kg‐1 lipids, 21.48 g·100 g‐1 total FAs, 3.48 and 13.03, respectively. The combination of process variable levels which maximised the desirability function (0.49 value) was ethanol/ethyl acetate (0.50:0.50, v/v) and led to values of 412.50 (g·kg‐1 lipids), 19.05 (g·100 g‐1 total FAs), 2.59 and 12.86, respectively, for the above‐mentioned lipid parameters. Results were compared to those obtained by the conventional chloroform/methanol procedure. By including an advanced mathematical design, a novel eco‐friendly strategy based on the employment of low‐toxicity solvents is proposed for the extraction from a marine waste substrate of highly valuable lipid compounds with healthy and nutritional properties.