Background: Tuberculosis (TB) is a major cause of morbidity and mortality in people living with HIV (PLWHIV). Isoniazid preventive therapy (IPT) prevents TB in PLWHIV, but estimates of its effects and actual implementation vary across countries. We reviewed studies that examined the impact of IPT on PLHIV and the factors influencing its implementation in Ethiopia. Methods: We searched PubMed/MEDLINE, Embase, and the Cochrane Central Register of Clinical Controlled Trials from their inception to 1 April 2021 for studies of any design that examined the impact of IPT on PLHIV and the factors influencing its implementation. The protocol was registered in PROSPERO, ID: CRD42021256579. Result: Of the initial 546 studies identified, 13 of which enrolled 12,426 participants, 15,640 PLHIV and 62 HIV clinical care providers were included. PLHIV who were on IPT, independently or simultaneously with ART, were less likely to develop TB than those without IPT. IPT interventions had a significant association with improved CD4 count and reduced all-cause mortality. IPT was less effective in people with advanced HIV infection. The major factors influencing IPT implementation and uptake were stock-outs, fear of developing isoniazid-resistant TB, patient's refusal and non-adherence, and improper counseling and low commitment of HIV clinical care providers. Conclusion: IPT alone or in combination with ART significantly reduces the incidence of TB and mortality in PLHIV in Ethiopia than those without IPT. More research on safety is needed, especially on women with HIV who receive a combination of IPT and ART. Additionally, studies need to be conducted to investigate the efficacy and safety of the new TPT (3 months combination of isoniazid and rifapentine) in children and people living with HIV.