Rho iso-alpha acids-rich extract (RIAA) from Humulus lupulus (hops) and proanthocyanidins-rich extracts (PAC) from Acacia nilotica exert anti-inflammatory and anti-diabetic activity in vitro and in vivo. We hypothesized that a combination of these two extracts would exert enhanced effects in vitro on inflammatory markers and insulin signaling, and on nonfasting glucose and insulin in db/db mice. Over 49 tested combinations, RIAA:PAC at 5:1 ($6.25{mu}g/mL$) exhibited the greatest reductions in $TNF{alpha}$-stimulated lipolysis and IL-6 release in 3T3-L1 adipocytes, comparable to $5{mu}g/mL$ troglitazone. Pretreatment of 3T3-L1 adipocytes with this combination ($5{mu}g/mL$) also led to a 3-fold increase in insulin-stimulated glucose uptake that was comparable to $5{mu}g/mL$ pioglitazone or $901{mu}g/mL$ aspirin. Finally, db/db mice fed with RIAA:PAC at 5:1 (100 mg/kg) for 7 days resulted in 22% decrease in nonfasting glucose and 19% decrease in insulin that was comparable to 0.5 mg/kg rosiglitazone and better than 100 mg/kg metformin. RIAA:PAC mixture may have the potential to be an alternative when conventional therapy is undesirable or ineffective, and future research exploring its long-term clinical application is warranted.