Noninvasive methods for assessing in-vivo skin blood perfusion parameters, such as hemoglobin oxygenation, are crucial for diagnosing and monitoring microvascular diseases. This approach is particularly beneficial for patients with compromised skin, where standard contact-based clinical devices are inappropriate. For this goal, we propose the analysis of multimodal data from an occlusion protocol applied to 18 healthy participants, which includes multispectral imaging of the whole hand and reference photoplethysmography information from the thumb. Multispectral data analysis was conducted using two different blind linear unmixing methods: principal component analysis (PCA), and extended blind endmember and abundance extraction (EBEAE). Perfusion maps for oxygenated and deoxygenated hemoglobin changes in the hand were generated using linear multivariable regression models based on the unmixing methods. Our results showed high accuracy, with R 2 -adjusted values, up to 0.90±0.08. Further analysis revealed that using more than four characteristic components during spectral unmixing did not improve the fit of the model. Bhattacharyya distance results showed that the fitted models with EBEAE were more sensitive to hemoglobin changes during occlusion stages, up to four times higher than PCA. Our study concludes that multispectral imaging with EBEAE is effective in quantifying changes in oxygenated hemoglobin levels, especially when using 3 to 4 characteristic components. Our proposed method holds promise for the noninvasive diagnosis and monitoring of superficial microvascular alterations across extensive anatomical regions.INDEX TERMS skin blood perfusion, hemoglobin, multispectral imaging, photoplethysmography, spectral unmixing.