Background: Numerous meta-analyses have assessed the efficacy of creatine supplementation in increasing muscle strength. However, most have not considered the effect of the participants’ age, training duration, or other confounding variables on strength outcomes. Therefore, the purpose of this study was to consider the effect of these variables on the potential efficacy of creatine supplementation and resistance training for improving measures of muscle strength. Methods: Four databases were searched (MEDLINE, Scopus, Embase, and SPORTDiscus) with a search end date of 22 May 2024. Twenty-three studies were included, with 20 studies involving males (447 male participants), 2 studies involving females (40 female participants), and 1 study involving both males and females (13 male participants and 9 female participants). Results: In comparison with a placebo, creatine supplementation combined with resistance training significantly increased upper-body (WMD = 4.43 kg, p < 0.001) and lower-body strength (WMD = 11.35 kg, p < 0.001). Subgroup analyses showed a trend for greater upper-body strength improvements for males on creatine compared with females on creatine (p = 0.067, Q = 3.366). Additionally, males who consumed creatine combined with resistance training significantly increased both upper- and lower-body strength, whereas females showed no significant gains. There was a trend indicating greater lower-body strength gains from high-dose creatine compared with lower doses (p = 0.068, Q = 3.341). No other variables influenced the effect of creatine supplementation. In conclusions, creatine supplementation with resistance training enhances upper- and lower-body muscle strength in adults aged < 50, with greater benefits likely to be seen in males than females.