Cadmium chloride (Cd) is a hazardous heavy metal known to impair antioxidant defenses and disrupt ion regulation in aquatic organisms. This study investigated the protective role of purslane (Portulaca oleracea, PUR), a medicinal plant rich in antioxidant bioactives, against Cd-induced oxidative stress and ion transporter dysfunction in Nile tilapia (Oreochromis niloticus). One hundred and eighty fish were divided into four groups (3 replicates per group, 15 fish/replicate): control, PUR (1% dietary inclusion), CdCl₂ (50 µg/L), and CdCl₂ + PUR, and exposed for 60 days. CdCl₂ exposure significantly elevated serum urea, uric acid, creatinine, glucose, and cortisol levels (by 67%, 20%, 78%, 54%, and 202%, respectively; P < 0.001), along with hypocalcemia (↓21%), hypermagnesemia (↑103%), and reduced serum iron (↓73%). Antioxidant enzyme activities in the gills were markedly suppressed (GPx (↓67%), CAT (↓67%), and SOD (↓61%)), with a depletion of GSH (↓58%) and an elevation of MDA (↑55%). The corresponding mRNA expressions of these enzymes in the kidney were downregulated (3.7–6.7-fold; P < 0.001). CdCl₂ also upregulated heat shock proteins hsp60, hsp70, and hsp90 in the kidney (5.7–8.4-fold; P < 0.001), indicating oxidative and cellular stress. Histopathological examination revealed pronounced tissue damage in the kidney and gill structures. Ion regulation was also disrupted by CdCl₂, as evidenced by reduced gill Ca2⁺-ATPase (↓81%) and Na⁺/K⁺-ATPase (↓75%) activities, along with significant downregulation of ion transporter genes (pc, nka-α3, atp6v1a, and slc4a4; 2.3–5.2-fold decrease). Furthermore, Cd residues in the gills increased dramatically, reaching approximately 76.6-fold higher levels compared to the control group. However, dietary PUR supplementation significantly alleviated these alterations, restoring enzyme activities, reducing hsp overexpression, repairing altered architecture, reducing Cd accumulation, and normalizing ion transporter function and gene expression (P < 0.001). In conclusion, PUR demonstrates strong protective effects against CdCl₂-induced oxidative damage and ionoregulatory dysfunction in O. niloticus, likely via antioxidant-mediated and cytoprotective mechanisms. These findings support PUR (1%) as a potential dietary strategy to enhance fish resilience under heavy metal stress. Future studies should explore the long-term effects of dietary PUR, assess dose-dependent responses, and investigate molecular signaling pathways involved in its protective action.