Motherwort (MW) is known for its renoprotective effects, but it has also been reported to potentially cause kidney damage. This study aimed to explore the distinct mechanisms underlying the protective and detrimental effects of MW on renal health, providing a theoretical basis for its safe clinical application. We explored the effects of MW in cisplatin-induced acute kidney injury (AKI) in BALB/c mice. We found that in AKI mice administration of the MW at doses of 10 and 40 g/kg for 4 days alleviated the loss of body weight, increased the renal index, reduced pathological kidney damage, and lowered the levels of blood urea nitrogen (BUN), serum creatinine (Scr), kidney injury molecule‑1 (KIM‑1), and neutrophil gelatinase‑associated lipocalin (NGAL). Proteomic analysis and subsequent validation indicated that the mechanisms were associated with ferroptosis and autophagy pathways. In healthy mice, short‑term MW treatment at the same doses (10 and 40 g/kg) did not affect renal function. However, when healthy mice were administered a higher dose of MW (80 g/kg) by gavage for an extended period (14 days), it induced body weight loss, triggered renal damage, and elevated BUN, Scr, KIM‑1, and NGAL levels. At this dosage, MW also increased oxidative stress, promoted apoptosis, and upregulated the expression of epidermal growth factor receptor (EGFR) pathway‑related proteins. Our findings demonstrate that MW plays a dual role in kidney protection and injury through distinct mechanisms, offering important guidance for its clinical application.