Mass production of microorganisms, algae among them, for new bioactive compounds and renewable innovative products is a current issue in biotechnology. The greatest challenge of basic research on this topic is to find the best solution for both physiology and scalability. In this study, the main goal was to highlight the contradictions of physiological and technological optimization in the same, relatively small, laboratory scale. The green alga Monoraphidium pusillum (Printz) Komárková-Legnorová was cultured in a conventional Erlenmeyer flask (as air bubbled in a tank-type photobioreactor) and in a hybrid (fermenter type + helical tubular type) photobioreactor of the same volume (2.8 L). Higher cell numbers from 1.7–2.3-fold, 2–2.8-fold higher dry masses, and 1.9–2.6-fold higher total lipid contents (mg·L−1) were measured in the tank reactor than in the hybrid reactor. Cultures in the conventional tank reactor were characterized with better nutrient utilization (42.8–77.7% higher phosphate uptake) and more diverse lipid composition than in the hybrid reactor. The study highlights that well-scalable arrangements and settings could be not optimal (or unsuitable in some cases) from a physiological point of view. The results suggest certain developmental directions for complex, well-scalable devices and highlight the importance of testing the gained physiological optima on these systems.