The role of heavy metals on human health has often been discussed regarding disease pathogenesis and risk factors. Alzheimer’s disease (AD), a prevalent neurodegenerative disease, is no exception. We conducted a comprehensive examination to assess the concentrations of lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) in biological samples of AD patients in comparison with a group of individuals without AD, with the objective of our study being to perform a systematic review on this topic. We performed this systematic review by searching various databases/search engines, including Web of Science, Scopus, PubMed, and Google Scholar, until December 7, 2022. Relevant studies were scrutinized for eligibility. Meta-analysis was performed on studies with sufficient data using STATA software. Twenty-seven out of 3349 studies met pre-defined eligibility criteria and were included in our systematic review. For the meta-analysis, 22 studies with 3346 participants (1291 AD patients and 2055 healthy controls) had sufficient data for inclusion in the analysis. Using a random-effects model, we found that pooled data indicated patients with AD had significantly higher levels of Cd in their biological samples compared to controls (Hedges’ g, 0.83; 95% CI, 0.11, 1.54; p = 0.023). However, other heavy metals were not significantly different in circulatory samples of AD patients compared to healthy controls (p > 0.05). This systematic review and meta-analysis indicated that Cd concentrations in AD patients were significantly higher than in healthy controls. Other included heavy metals may not be directly associated with increased risk of AD.