Nanoplastics (NPs) are emerging environmental contaminants that can enter the body via ingestion, inhalation, or dermal exposure and accumulate in organs, causing damage. Although renal toxicity of NPs has been reported, the mechanisms remain unclear. We first tested whether toxicity differs by surface charge. Among polystyrene NPs, cationic particles showed the strongest cytotoxicity in renal tubular epithelial cells and were therefore used in mouse studies. Oral administration of cationic NPs (10, 50, or 200 mg/kg) for 2 or 6 weeks revealed that short-term exposure caused little renal damage, whereas long-term exposure induced tubular injury. RNA-seq of kidneys from NP-treated mice showed downregulation of oxidative phosphorylation (OXPHOS)–related genes, confirmed at mRNA and protein levels. Because mitochondrial dysfunction can activate the STING pathway, we examined STING signaling and found increased activation with inflammatory responses in NP-treated kidneys. Consistently, NP exposure in NRK52E cells caused mitochondrial impairment, STING activation, and inflammation. Chronic mitochondrial dysfunction and inflammation are known drivers of senescence, and NP exposure induced senescence phenotypes in NRK52E cells and kidneys with mild fibrosis. Pharmacological inhibition of STING with C-176 reduced inflammation but did not restore mitochondrial function or senescence. In contrast, activation of PGC1α with ZLN005 rescued mitochondrial function and alleviated NP-induced senescence in vitro. In summary, cationic NPs impair mitochondria in renal tubular epithelial cells, leading to inflammation, senescence, and renal dysfunction. PGC1α activation mitigates these effects, highlighting mitochondria as a therapeutic target in NP-associated nephrotoxicity.