We evaluated the efficacy, safety, adherence, quality of life (QoL) and cost-effectiveness of long-acting growth hormone (LAGH) vs daily growth hormone (GH) preparations in the treatment of growth hormone deficiency (GHD) in children. Systematic searches were performed in PubMed, Embase and Web of Science up to July 2022 on randomized and non-randomized studies involving children with GHD receiving LAGH as compared to daily GH. Meta-analyses for efficacy and safety were performed comparing different LAGH/daily GH formulations. From the initial 1393 records, we included 16 studies for efficacy and safety, 8 studies for adherence and 2 studies for QoL. No studies reporting cost-effectiveness were found. Pooled mean differences of mean annualized height velocity (cm/year) showed no difference between LAGH and daily GH: Eutropin Plus® vs Eutropin® − 0.14 (−0.43, 0.15), Eutropin Plus® vs Genotropin® − 0.74 (−1.83, 0.34), Jintrolong® vs Jintropin AQ® 0.05 (−0.54, 0.65), Somatrogon vs Genotropin® − 1.40 (−2.91, 0.10), TransCon vs Genotropin® 0.93 (0.26, 1.61). Also, other efficacy and safety outcomes, QoL and adherence were comparable for LAGH and daily GH. Our results showed that, although most of the included studies had some concerns for risk of bias, regarding efficacy and safety all the LAGH formulations were similar to daily GH. Future high quality studies are needed to confirm these data. Adherence and QoL should be addressed from real-world data studies for both the mid and long term and in a larger population. Cost-effectiveness studies are needed to measure the economic impact of LAGH from the healthcare payer’s perspective. Display omitted •Therapy with Long-acting GH preparations (LAGH) reduces the frequency of administration of GH.•Pooled mean differences of mean annualized height velocity showed no difference between LAGH and daily GH.•Safety outcomes were comparable for LAGH and daily GH.•Quality of life in children taking LAGH was similar to that of children using daily GH.•As is observed in RCTs, adherence was similarly high with daily GH and weekly GH.