Toxic heavy metals (THMs) are non-essential hazardous environmental pollutants with intractable health challenges in humans and animals. Exposure to lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), nickel (Ni), and chromium (Cr) are ubiquitous and unavoidable due to food contamination, mining, and industrial mobilization. They are triggers of tissue impairment and aberrant signaling pathways that cascade into several toxicities and pathologies. Each of Pb, Cd, Hg, As, Ni, and Cr aggravate oxidative inflammation, protein dysregulation, apoptotic induction, DNA damage, endocrine deficits, and mitochondrial dysfunction contributing to the pathophysiology of diseases. Hesperidin (HSD) and hesperetin (HST) are flavonoids from citrus fruits, and systematic investigations suggest their potential to combat the molecular alterations and toxicities induced by THMs. They mitigate heavy metal toxicity via antioxidant, anti-inflammatory, and anti-apoptotic effects via scavenging free radicals and modulation of ATPases, cell cycle proteins, and various cellular signaling pathways, including Nrf2/HO-1/ARE, PI3K/mTOR/Akt, MAPK/caspase-3/Bax/Bcl-2, iNOS/NF-κB/TNF-α/COX-2. This review summarized the mechanistic effects of heavy metal toxicity and the insights on molecular mechanisms underlying mitigation of heavy metal toxicity by HSD and HST. Hesperidin and hesperetin are potential flavonoids for the modulation of pathological signaling networks associated with THMs. Therefore, HSD and HST can be suggested as natural dietary agents and blockers of harmful effects of THMs.