Intracellular calcium levels regulate a wide range of cellular processes and are therefore tightly controlled by ion channels and transporters. One key regulator is the sarco/endoplasmic reticulum calcium ATPase (SERCA), a transmembrane P-type ATPase that actively transports calcium ions from the cytosol into intracellular stores. Subsequent calcium release from these stores triggers physiologically critical events, such as muscle contraction. Small-molecule modulators of SERCA activity are valuable tools for probing calcium signaling, enabling rapid manipulation of intracellular calcium levels, and also hold therapeutic promise for diseases associated with dysregulated calcium homeostasis, including heart disease and diabetes. In this study, we used the quinolone CDN1163 and the natural product gingerol as scaffolds for the design of novel allosteric SERCA activators. A total of 20 CDN1163 analogs and 16 gingerol analogs were synthesized and evaluated for their ability to modulate SERCA activity, establishing structure-activity relationships. The most active compounds displayed sub-micromolar potency and enhanced enzyme activity by up to 40%. Structure-based methods complemented the synthetic and experimental studies, providing mechanistic insight and guiding the design of SERCA activators with improved properties.