Background Transthyretin cardiac amyloidosis (ATTR‐CMP) is an increasingly recognized and treatable cause of heart failure with preserved ejection fraction. Multimodality cardiac imaging is recommended for ATTR‐CMP diagnosis, but its cost‐effectiveness in current clinical practice has not been well studied. Methods and Results Using a microsimulation model, we compared the cost‐effectiveness of a combination of strategies involving ^99m technetium pyrophosphate (PYP), cardiac magnetic resonance imaging, and endomyocardial biopsy for the diagnosis of ATTR‐CMP. We developed a decision analytic model to project health care costs and lifetime quality‐adjusted life years for symptomatic, older patients who present with congestive heart failure, with an increased left ventricular wall thickness and a 13% prevalence of ATTR‐CMP. Rates of clinical events, costs, and quality‐of‐life values were estimated from published literature. The analysis was conducted from a US health care system perspective with health and cost outcomes discounted annually at 3%. In the base‐case scenario, using a fixed tafamidis price of $16 000 annually (previously identified cost‐effective price), total health care costs per person were lowest for the PYP‐only strategy ($209 415) and highest for endomyocardial biopsy strategy ($215 881). Of the 7 strategies examined, the PYP‐only strategy had the highest net monetary benefit using a willingness‐to‐pay threshold of $100 000/quality‐adjusted life year. Results were sensitive to variations in model inputs for PYP and cardiac magnetic resonance imaging specificity, cost of tafamidis, and willingness‐to‐pay thresholds. Conclusions Our model‐based analyses showed that a PYP‐only strategy to diagnose ATTR‐CMP is the most cost‐effective strategy, at willingness‐to‐pay threshold of $100 000/quality‐adjusted life year. At higher threshold ($150 000/quality‐adjusted life year), sequential tests involving PYP and cardiac magnetic resonance imaging may be considered cost effective.