Background: Small-sided soccer games (SSSG) are a specific exercise regime with two small teams playing against each other on a relatively small pitch. There is evidence from original research that SSSG exposure provides performance and health benefits for untrained adults. Objectives: The aim of this systematic review was to summarize recent evidence on the acute and long-term effects of SSSG on physical fitness, physiological responses, and health indices in healthy untrained individuals and clinical populations. Methods: This systematic literature search was conducted in four electronic databases (PubMed, Web of Science, SPORTDiscus) from inception until June 2019. The following key terms (and synonyms searched for by the MeSH database) were included and combined using the operators “AND”, “OR”, “NOT”: ((soccer OR football) AND (“soccer training” OR “football training” OR “soccer game*” OR “small-sided soccer game*”) AND (“physical fitness” OR “physiological adaptation*” OR “physiological response*” OR health OR “body weight” OR “body mass” OR “body fat” OR “bone composition” OR “blood pressure”)). The search syntax initially identified 1145 records. After screening for titles, abstracts, and full texts, 41 studies remained that examined the acute (7 studies) and long-term effects (34 studies) of SSSG-based training on physical fitness, physiological responses, and selected alth indices in healthy untrained individuals and clinical populations. Results: No training-related injuries were reported in the 41 acute and long-term SSSG studies. Typically, a single session of SSSG lasted 12–20 min (e.g., 3 × 4 min with 3 min rest or 5 × 4 min with 4 min rest) involving 4–12 players (2 vs. 2 to 6 vs. 6) at an intensity ≥ 80% of HRmax. Following single SSSG session, high cardiovascular and metabolic demands were observed. Specifically, based on the outcomes, the seven acute studies reported average heart rates (HR) ≥ 80% of HRmax (165–175 bpm) and mean blood lactate concentrations exceeding 5 mmol/l (4.5–5.9 mmol/l) after single SSSG sessions. Based on the results of 34 studies (20 with healthy untrained, 10 with unhealthy individuals, and 4 with individuals with obesity), SSSG training lasted between 12 and 16 weeks and was performed 2–3 times per week. SSSG had positive long-term effects on physical fitness (e.g., Yo–Yo IR1 performance), physiological responses including maximal oxygen uptake (VO2max) [+ 7 to 16%], and many health-related markers such as blood pressure (reductions in systolic [− 7.5%] and diastolic [− 10.3%] blood pressure), body composition (decreased fat mass [− 2 to − 5%]), and improved indices of bone health (bone mineral density: [+ 5 to 13%]; bone mineral content: [+ 4 to 5%]), and metabolic (LDL-cholesterol [− 15%] as well as cardiac function (left-ventricular internal diastolic diameter [+ 8%], end diastolic volume [+ 21%], left-ventricular mass index [+ 18%], and left-ventricular ejection fraction [+ 8%]). Irrespective of age or sex, these health benefits were observed in both, untrained individuals and clinical populations. Conclusions: In conclusion, findings from this systematic review suggest that acute SSSG may elicit high cardiovascular and metabolic demands in untrained healthy adults and clinical populations. Moreover, this type of exercise is safe with positive long-term effects on physical fitness and health indices. Future studies are needed examining the long-term effects on physical fitness and physiological adaptations of different types of SSSG training (e.g., 3 vs. 3; 6 vs. 6) in comparison to continuous or interval training in different cohorts.