This systematic review determines the efficacy and safety of duloxetine for chronic low back pain (CLBP). We queried the PubMed, SCOPUS, and Ovid MEDLINE databases. All level I and II randomized controlled studies published in the English language investigating the efficacy of duloxetine for chronic low back pain were included. Five studies (832 duloxetine-treated patients, 667 placebo-treated patients, and 41 duloxetine and placebo crossover analysis patients) were analyzed. One study was level I evidence and four studies were level II evidence. All five studies reported statistically significant improvements in more than one back-pain-specific clinical outcome score with duloxetine versus placebo. Four studies found that duloxetine 60 mg daily leads to one or more statistically significant improvements versus placebo in Brief Pain Inventory Severity (BPI-S) scores. All five studies found no significant difference in serious adverse events (AEs) between the duloxetine and placebo groups. One study found a higher rate of total AEs among the duloxetine 120 mg group versus the placebo group; however, the same study did not find a significant difference in total AEs among duloxetine 20 mg and 60 mg groups versus placebo. Duloxetine is a safe and effective first-line option for the treatment of CLBP. Current studies demonstrate that 60 mg taken once daily has the highest efficacy for reducing pain and disability while minimizing minor adverse effects. Further randomized controlled trials with long-term follow-up are necessary to determine its long-term effects.