The liver is a critical organ in the human body and is frequently exposed to numerous exogenous toxic substances, including silver nanoparticles (AgNPs). This study aimed to examine the anti-inflammatory, anti-angiogenic, and hepatoprotective effects of Withania somnifera (W. somnifera) extract on AgNP-induced liver toxicity in Swiss mice. Fifty mice were divided into five groups. Group I (negative control) consisted of ten mice. Group II received oral W. somnifera extracts (80 mg/kg/bw) for 14 days. Group III was injected intraperitoneally (i.p.) with AgNPs at a daily dose of 35 mg/kg/bw for 3 days. Group IV received i.p. AgNPs for 3 days, followed by saline for 14 days. Group V received i.p. AgNPs for 3 days, followed by oral W. somnifera (80 mg/kg/bw) for 14 days. Liver function tests, pro and anti-inflammatory cytokines, antioxidant activities, protein carbonyl (PC) levels, liver histopathological analysis, immunohistochemical expressions of transcription factor (NF-κB), and vascular endothelial growth factor (VEGF) were examined. Group III had elevated levels of liver function, a significant increase of pro and anti-inflammatory cytokines, antioxidant activity, and PC levels. Histological observations revealed congested sinusoids filled with red blood cells (RBCs) and hepatocyte necrosis. Also, positive expressions of NF-κB and VEGF were detected compared with Group I. However, the administration of W. somnifera to Group V revealed significant changes with evident improvements in liver function biomarkers, pro and anti-inflammatory cytokines, antioxidant activities, oxidative stress markers (PC), and histopathological and immunohistochemical parameters compared to Group III. The results revealed that W. somnifera has promising and potential hepatoprotective, anti-inflammatory, and anti-angiogenic effects against liver toxicity. Further detailed studies are recommended to explore the potential of W. somnifera as a treatment for human liver ailments.