To commercialize large‐scale and high‐density microalgae cultivation, a 10L cross‐flow flat‐plate airlift photobioreactor (CFA‐PBR) was designed and amplified to two types of 40L CFA‐PBRs via different scaling‐up methods. The multiphase flow characteristics and bioreaction process of these CFA‐PBRs were studied by experiments and computational fluid dynamics (CFD) simulation. The results show that the parameters of CFA‐PBRs, such as bubble size, gas holdup, mass transfer, and photosynthetic reaction efficiency, mainly conform to the principle of geometric similarity under the same light thickness and superficial gas velocity, which is significant for large‐scale industrial applications of the efficient high‐density algae cultivation.