Purpose: To compare the influence of immediate loading (IL) and non-immediate loading (NIL) protocols on overdentures retained by reduced-diameter implants (≤ 3.5 mm). Materials and Methods: Electronic databases including MEDLINE (via PubMed), Embase, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) comparing clinical outcomes of immediately loaded and non-immediately loaded reduced-diameter implants supporting overdentures. The risk of bias within and across the studies and the certainty of evidence were assessed by RoB 2.0 and GRADE, respectively. A sensitivity analysis was performed by eliminating studies at high risk of bias and repeating the data synthesis employing the random effects model. Subgroup analyses were conducted based on the implant diameter and the length of follow-up. Results: Overall, six RCTs with 255 patients were included in this systematic review. The meta-analyses found similar implant survival rates between immediately loaded and non-immediately loaded implants in the mini-implant (RR = 0.98; 95% CI = 0.95, 1.01; P = .12) and narrow-diameter implant subgroups (RR = 0.99; 95% CI = 0.94, 1.03; P = .56) as well as in short-term (RR = 0.98; 95% CI = 0.97, 1.00; P = .11) and long-term (RR = 0.97; 95% CI = 0.93, 1.01; P = .09) follow-up subgroups. Additionally, marginal bone loss (MBL) showed no statistically significant difference between the loading protocols in the subgroup of long-term follow-up (MD = 0.03; 95% CI = –0.16, 0.23; P = .74). Three RCTs investigating peri-implant parameters found relatively higher modified plaque index (PI) and probing depth (PD) in reduced-diameter implants under IL. Conclusions: Compared with NIL, the IL protocol can achieve comparable survival rates and MBL in reduced-diameter implants supporting overdentures.