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Background/Objectives: Erectile dysfunction (ED) is a prevalent and multifactorial condition influenced by psychological and sleep-related factors. This study aimed to evaluate the independent and combined contributions of insomnia and antidepressant use to the risk of ED. Methods: A case-control study was conducted including adult men with and without ED. Logistic regression was used to estimate crude and adjusted odds ratios (ORs). A stepwise multivariable model (entry p < 0.5, exit p < 0.1) identified significant predictors. Effect modification was explored through stratified analyses and additive interaction indices: relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S). Results: Insomnia (adjusted OR 1.98; 95% CI 1.09–3.60; p = 0.026) and antidepressant use (adjusted OR 2.04; 95% CI 1.12–3.72; p = 0.021) were each independently associated with ED. Participants with both exposures had a markedly higher risk (adjusted OR 3.94; 95% CI 1.67–9.26; p = 0.002). However, interaction indices (RERI ≈ 0.03; S ≈ 1.01) suggested no statistically significant synergistic interaction. The combined effect approximated the sum of individual effects, indicating an additive rather than synergistic relationship. Conclusions: Both insomnia and antidepressant use independently increased the odds of ED. Although no significant statistical interaction was found, their co-occurrence was associated with a substantially higher risk, underscoring the clinical importance of evaluating and addressing both factors in the management of ED.