Retrieval of the phycocyanin concentration (PC), a characteristic pigment of, and proxy for, cyanobacteria biomass, from hyperspectral satellite remote sensing measurements is challenging due to uncertainties in the remote sensing reflectance (∆Rrs) resulting from atmospheric correction and instrument radiometric noise. Although several individual algorithms have been proven to capture local variations in cyanobacteria biomass in specific regions, their performance has not been assessed on hyperspectral images from satellite sensors. Our work leverages a machine-learning model, Mixture Density Networks (MDNs), trained on a large (N = 939) dataset of collocated in situ chlorophyll-a concentrations (Chla), PCs, and remote sensing reflectance (Rrs) measurements to estimate PC from all relevant spectral bands. The performance of the developed model is demonstrated via PC maps produced from select images of the Hyperspectral Imager for the Coastal Ocean (HICO) and Italian Space Agency's PRecursore IperSpettrale della Missione Applicativa (PRISMA) using a matchup dataset. As input to the MDN, we incorporate a combination of widely used band ratios (BRs) and line heights (LHs) taken from existing multispectral algorithms, that have been proven for both Chla and PC estimation, as well as novel BRs and LHs to increase the overall cyanobacteria biomass estimation accuracy and reduce the sensitivity to ∆Rrs. When trained on a random half of the dataset, the MDN achieves uncertainties of 44.3%, which is less than half of the uncertainties of all viable optimized multispectral PC algorithms. The MDN is notably better than multispectral algorithms at preventing overestimation on low (<10 mg m−3) PC. Visibly, HICO and PRISMA PC maps show the wider dynamic range that can be represented by the MDN. The available in situ and satellite-derived Rrs matchups and measured in situ PC demonstrate the robustness of the MDN for estimating low (<10 mg m−3) PC and the reduced impact of ∆Rrs on medium-to-high in situ PC (>10 mg m−3). According to our extensive assessments, the developed model is anticipated to enable practical PC products from PRISMA and HICO, therefore the model is promising for planned hyperspectral missions, such as the Plankton Aerosol and Cloud Ecosystem (PACE). This advancement will enhance the complementary roles of hyperspectral radiometry from satellite and low-altitude platforms for quantifying and monitoring cyanobacteria harmful algal blooms at both large and local spatial scales.