Doxycycline is among the most commonly used antibiotics for the treatment and long-term suppression of musculoskeletal infections such as osteomyelitis and periprosthetic joint infection. We systematically reviewed clinical trials and cohort studies that examined outcomes of musculoskeletal infections treated with doxycycline. Eligible studies were published in Medline or Embase in English before March 2, 2021. Eleven reports were included; eight addressed medical/non-dental infections, and three addressed dental infections. Brucella was the most frequently studied organism in the non-dental studies. Random-effects meta-analyses showed no significant difference in Brucella relapse risk after six weeks of treatment with 200 mg doxycycline compared to 400 mg ofloxacin daily (pool risk ratio: 0.94, 95% confidence interval: 0.2 - 4.45, I2 = 0%). Despite a large number of case reports, case series, and cross-sectional studies on this topic, few studies investigated doxycycline treatment outcomes; and evidence was largely limited to rare infections such as Brucella.