Background: More data are needed about the safety of antibiotic de-escalation in specific clinical situations as a strategy to reduce exposure to broad-spectrum antibiotics. This study aims to compare the survival curve of patient de-escalated (early or late) against those not de-escalated on antibiotics, to determine the association of patient related, clinical related, and pressure sore/device related characteristics on all-cause 30-day mortality and determine the impact of early and late antibiotic de-escalation on 30-day all-cause mortality. Methods: This is a retrospective cohort study on patients in medical ward Hospital Kuala Lumpur, admitted between January 2016 and June 2019. A Kaplan–Meier survival curve and Fleming–Harrington test were used to compare the overall survival rates between early, late, and those not de-escalated on antibiotics while multivariable Cox proportional hazards regression was used to determine prognostic factors associated with mortality and the impact of de-escalation on 30-day all-cause mortality. Results: Overall mortality rates were not significantly different when patients were not de-escalated on extended or restricted antibiotics, compared to those de-escalated early or later (p = 0.760). Variables associated with 30-day all-cause mortality were a Sequential Organ Function Assessment (SOFA) score on the day of antimicrobial stewardship (AMS) intervention and Charlson’s comorbidity score (CCS). After controlling for confounders, early and late antibiotics were not associated with an increased risk of mortality. Conclusion: The results of this study reinforce that restricted or extended antibiotic de-escalation in patients does not significantly affect 30-day all-cause mortality compared to continuation with extended and restricted antibiotics.