Toxoplasmosis is a globally prevalent zoonotic parasitic disease. Neonates with congenital infection can develop severe long-term sequelae, which can be mitigated or prevented through early diagnosis and therapeutic approaches. In this context, the main objective of this study was to describe the main treatments and evaluate the effectiveness of the current treatment protocols for gestational and congenital toxoplasmosis to prevent vertical transmission and to reduce clinical manifestations in neonates. This systematic review with a meta-analysis searched digital databases (PUBMED, SCOPUS, WEB OF SCIENCE, EMBASE, and COCHRANE) for observational cohort studies published between 1 January 2013 and 29 January 2025, evaluating treatment effectiveness in gestational and congenital toxoplasmosis. Risk ratios (RRs) were calculated using random effects models to assess infection risk and clinical manifestations in neonates. The study quality was assessed following the Joanna Briggs Institute protocol and fifty-six studies from 16 countries were included, comprising 11,090 pregnant women and 4138 children. Studies were predominantly from Brazil (38%), France, and Italy. Only 9% of the studies indicated knowledge of the serological status of the pregnant woman before the gestational stage. Of 10,148 women with confirmed toxoplasmosis, 8600 received treatment, with 18% of their children infected, compared to a 58% infection rate in untreated mothers’ children. Meta-analysis showed that treatment reduced infection risk (RR = 0.34 [0.21; 0.57]) and clinical manifestations (RR = 0.30 [0.17; 0.56]). While spiramycin or triple therapy showed similar effects, triple therapy demonstrated more consistent results (RR: 0.22 [0.15; 0.32]) compared to spiramycin alone (RR: 0.54 [0.06; 4.67]). In conclusion, treatment protocols for congenital or gestational toxoplasmosis have proven to be effective in reducing the risk of infection and clinical manifestations in neonates. Regarding the type of treatment, although they have similar responses, the use of triple therapy shows more consistent responses than isolated spiramycin. It can be also concluded that prevention and mitigation of congenital toxoplasmosis require standardized treatment protocols, improved diagnostic methods, and educational programs for women of childbearing age, as treatment initiation timing and protocol choice are crucial factors in determining outcomes.