Experimental and clinical studies indicate that uric acid is associated with several risk factors of chronic kidney disease including diabetes, hypertension, oxidative stress, inflammation, and hyperuricemia. Clerodendrum trichotomum leaves and stems have been used in folk medicine for their anti-hypertension, arthritis, rheumatism, and anti-inflammatory properties. This study was performed to explore the potential of C. trichotomum leaves as an anti-hyperuricemic agent. The hot water extract of C. trichotomum leaves (HW) showed higher antioxidant activities and total polyphenol contents comparing with its ethanol extract. Then, we investigated whether HW have the anti-inflammatory and cytoprotective effects in in vitro and in vivo hyperuricemia models. When RAW 264.7 cells were treated with lipopolysaccharide (LPS) and soluble uric acid, HW suppressed nitric oxide (NO) production and the expression of iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2), and it increased the expression of HO-1 (heme oxygenase-1). In uric acid treated HK-2 cells, HW decreased the expression of Bax (Bcl-2-associated X), PARP-1 [poly (ADP-ribose) polymerase-1] and cleaved caspase-3, while it increased Bcl-2 (B-cell lymphoma 2) protein. In potassium oxonate (PO)-induced mice, HW decreased the levels of serum uric acid, serum creatinine and blood urea nitrogen (BUN), but it increased urine uric acid and urine creatinine. Furthermore, HW decreased the expression of iNOS, COX-2, tumor necrosis factor-α (TNF-α), Bax, cleaved caspase-3 and PARP-1 and it increased the expression of Bcl-2 protein in PO-induced mice kidney. Immunohistochemical analysis showed that HW decreased the TNF-α expression in PO-induced mice liver. In addition, RNA sequencing analysis using liver tissues showed that HW restored the expression profiles of genes implicated in inflammatory and cytoprotective pathways. Taken together, these results suggest that HW have a potential for prevention and treatment of hyperuricemia by exerting anti-inflammatory and cytoprotective effects.