Two-dimensional (2D) perovskites incorporating large organic spacer cations between the octahedral anion layers exhibit exceptional optoelectronic properties and structural tunability. Given the limited availability of commercial spacer cations, mixing different cations within a single perovskite structure becomes an intriguing prospect. However, clear principles for selecting compatible spacer combinations are still lacking. To address this, we explore three guiding principles: solubility, interlayer distance, and Pb-I-Pb bond angle. Guided by those principles, we choose five spacer cations with a variety of shapes and sizes: BA = butylammonium, IPA = 3-iodopropyl ammonium, CPA = cyclopentylammonium, DAO = 1,8-diammonium octane, PA = pentylammonium, and successfully synthesize five new mixed-spacer 2D perovskites, including (BA)(IPA)PbI4, (CPA)(IPA)PbI4, (BA)(CPA)PbI4, (DAO)0.5(CPA)PbI4, and (DAO)0.5(PA)PbI4. Our findings show that mixing spacers can lead to higher symmetry, significantly suppress out-of-plane tilting, and give rise to a unique rippling structure in some systems. The optical bandgaps of the mixed-spacer 2D perovskites are typically located between those of the two parent phases. Finally, we extend this approach to systems incorporating up to five spacers in a single system, with phase purity confirmed through powder and single-crystal X-ray diffraction characterizations. This work offers simple yet practical indicators for selecting compatible spacer cations, providing a pathway to better understand how spacer mixing influences the structural, physical, and optical properties of 2D perovskites.