The donor-dependent supply of platelets is frequently insufficient to meet transfusion needs. To address this issue, we developed a clinically applicable strategy for the derivation of functional platelets from human pluripotent stem cells (PSCs). This approach involves the establishment of stable immortalized megakaryocyte progenitor cell lines (imMKCLs) from PSC-derived hematopoietic progenitors through the overexpression of BMI1 and BCL-XL to respectively suppress senescence and apoptosis and the constrained overexpression of c-MYC to promote proliferation. The resulting imMKCLs can be expanded in culture over extended periods (4–5 months), even after cryopreservation. Halting the overexpression of c-MYC, BMI1, and BCL-XL in growing imMKCLs led to the production of CD42b+ platelets with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo. The combination of robust expansion capacity and efficient platelet production means that appropriately selected imMKCL clones represent a potentially inexhaustible source of hPSC-derived platelets for clinical application. Display omitted •Expandable megakaryocyte progenitors were established from human PSCs•BMI1 and BCL-XL suppress senescence and apoptosis induced by c-MYC in imMKCLs•imMKCLs differentiate into mature megakaryocytes and release functional platelets•Rapid and efficient platelet yield provides key advantages for clinical application This study describes a clinically applicable strategy for the derivation of functional platelets from human induced pluripotent stem cells (iPSCs) using the establishment of stable immortalized megakaryocyte progenitor lines from the iPSCs.