Heart failure (HF) remains a major public health burden, with current therapies focused primarily on symptom management. Impaired activity of the cardiac Ca pump SERCA2a is a hallmark of HF and a promising therapeutic target, but limited structural data have hindered small-molecule development. Here, we report a comprehensive structure-activity relationship (SAR) investigation of small-molecule SERCA2a activators, beginning with natural product hits and progressing through iterative optimization of three pharmacophoric regions. This effort produced the largest collection of SERCA2a modulators to date─including 20 activators, 8 dual effectors, and 6 inhibitors. Several indoline, benzofuran, and benzodioxole analogs emerged as potent activators, increasing ATPase activity by ∼57% (EC = 0.7-9 μM). Notably, SERCA2a activation was inversely correlated with Ca affinity, suggesting that SERCA2a stimulation occurs at the expense of Ca binding. In summary, these findings identify key structural features that drive SERCA2a activity and establish a framework for developing next-generation SERCA2a-targeted therapies.