© 2020 Elsevier B.V. The rapidly growing technological demand for lithium-ion batteries has prompted the development of novel cathode materials with high energy density, low cost, and improved safety. High voltage spinel, LiNi0.5Mn1.5O4 (LNMO), is one of the most promising candidates yet to be commercialized. The two primary obstacles for this material are the inferior electronic conductivity and fast capacity degradation in full cells due to the high operating voltage. By systematically addressing these limitations, we successfully develop a thick LNMO electrode with areal capacity loadings up to 3 mAh·cm−2. The optimized thick electrode is paired with a commercial graphite anode at both the coin cell and pouch cell level, achieving a full cell capacity retention as high as 72% and 78%, respectively, after 300 cycles. We attribute this superior cycling stability to careful optimizations of cell components and testing conditions, with a specific focus improving electronic conductivity and high voltage compatibility. These results suggest precise control of materials quality, electrode architecture and electrolyte optimization can soon support the development of a cobalt-free battery system based on a thick LNMO cathode (>4 mAh·cm2), which will eventually meet the needs of next-generation Li-ion batteries with reduced cost, improved safety, and assured sustainability.