The known neuroprotective effects of minocycline and creatine in animal models of amyotrophic lateral sclerosis (ALS) led us to examine whether the combination of these agents would result in increased neuroprotection. As previously reported, we confirmed in ALS mice that either minocycline or creatine treatment results in improvement in motor performance and extended survival. We report that combination of minocycline and creatine resulted in additive neuroprotection, suggesting this to be a novel potential strategy for the treatment of ALS. To our knowledge, this is the first report demonstrating additive neuroprotection of a combinatorial approach in a mouse model of ALS. Adding relevancy to our findings, minocycline and creatine, are relatively safe, cross the blood-brain barrier, and are currently available for human evaluation.