Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive infiltrative cardiomyopathy associated with substantial morbidity and mortality. This systematic review evaluates the effects of tafamidis on echocardiographic parameters, cardiac biomarkers, functional outcomes, mortality, and safety in patients with ATTR-CM. Methods: This systematic review was conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420261391553). PubMed, Embase, and Web of Science were searched through 20 March 2026. Eligible studies included adults with ATTR-CM treated with tafamidis and reporting, echocardiographic, biomarker, functional, mortality, or safety outcomes. Randomized controlled trials and observational studies were included. Risk of bias was assessed using the Cochrane RoB 2 tool and Newcastle–Ottawa Scale. Due to substantial heterogeneity, a narrative synthesis was performed. Results: Seventeen studies were included with a total of 1890 patients. Tafamidis treatment was potentially associated with stabilization of global longitudinal strain, preservation of functional status, and lower all-cause mortality compared with untreated or control cohorts. Biomarker findings, including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT), were heterogeneous and did not demonstrate a consistent pattern of improvement. Functional outcomes, including New York Heart Association (NYHA) class, 6-minute walk distance (6MWT), National Amyloidosis Center (NAC) staging, and quality-of-life measures, suggested slower clinical deterioration among treated patients. Limited available safety data indicated that tafamidis was generally well tolerated, with no major safety concerns identified. Conclusions: Current evidence may suggest that tafamidis slows disease progression and may potentially be associated with improved survival in ATTR-CM. Further prospective studies with standardized outcome reporting are needed. Evidence was limited by heterogeneity in study design, outcome reporting, and follow-up duration, with most included studies being observational.