Lenalidomide is a drug that has immune-modulating, anti-angiogenic, and anti-inflammatory properties. In this study, we developed green HPLC and spectrophotometric methods to determine the concentration of lenalidomide in pure and pharmaceutical formulations. In the HPLC method, 10 mM potassium dihydrogen phosphate solution (pH: 2.0) and ethanol (50:50, V/V) were used as mobile phases, isocratic elution was applied at a flow rate of 1.0 mL min−1 and detection was made at 304 nm. In the spectrophotometric method, the spectral patterns of standard solutions in different solvents were comprehensively examined, the best spectra were obtained with ultrapure water, and a wavelength of 304 nm was selected for detection. Both methods have been validated according to ICH guidelines for various parameters. Correlation coefficients greater than 0.999 were determined for both methods in the concentration range of 5–30 μg mL−1. The developed methods were applied to commercial formulations, and comparisons of the results were made using the Student (t) test for means and the Fischer (F) test for standard deviations. No statistically significant difference was observed between the methods. The greenness evaluation of these methods was carried out using AGREE software. The developed methods are proposed as excellent environmental and operator-friendly alternatives for the quantification of Lenalidomide in pharmaceutical formulations.