Short-term energy deficits impair anabolic hormones and muscle protein synthesis. However, the effects of prolonged energy deficits on resistance training (RT) outcomes remain unexplored. Thus, we conducted a systematic review of PubMed and SportDiscus for randomized controlled trials performing RT in an energy deficit (RT+ED) for ≥3 weeks. We first divided the literature into studies with a parallel control group without an energy deficit (RT+CON; Analysis A) and studies without RT+CON (Analysis B). Analysis A consisted of a meta-analysis comparing gains in lean mass (LM) and strength between RT+ED and RT+CON. Studies in Analysis B were matched with separate RT+CON studies for participant and intervention characteristics, and we qualitatively compared the gains in LM and strength between RT+ED and RT+CON. Finally, Analyses A and B were pooled into a meta-regression examining the relationship between the magnitude of the energy deficit and LM. Analysis A showed LM gains were impaired in RT+ED vs RT+CON (effect size (ES) = −0.57, p = 0.02), but strength gains were comparable between conditions (ES = −0.31, p = 0.28). Analysis B supports the impairment of LM in RT+ED (ES: −0.11, p = 0.03) vs RT+CON (ES: 0.20, p < 0.001) but not strength (RT+ED ES: 0.84; RT+CON ES: 0.81). Finally, our meta-regression demonstrated that an energy deficit of ~500 kcal · day−1 prevented gains in LM. Individuals performing RT to build LM should avoid prolonged energy deficiency, and individuals performing RT to preserve LM during weight loss should avoid energy deficits >500 kcal day−1.