Depression is common in older adults and those with cardiovascular disease. Although selective serotonin reuptake inhibitors generally have been shown to be safe to treat depression in these patients, it is important to identify additional antidepressants when selective serotonin reuptake inhibitors are not effective. This qualitative narrative review summarizes what is known about the cardiovascular side effects of some of the newer antidepressants. Twelve novel non-selective serotonin reuptake inhibitor antidepressants were identified from the literature: venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, mirtazapine, bupropion, vilazodone, vortioxetine, agomelatine, moclobemide, and ketamine–esketamine. A search restricted to publications written in English was conducted in PubMed and Google Scholar with the following search criteria: the specific antidepressant AND (QT OR QTc OR “heart rate” OR “heart rate variability” OR “hypertension” OR “orthostatic hypotension” OR “cardiovascular outcomes” OR “arrhythmia” OR “myocardial infarction” OR “cardiovascular mortality”) AND (geriatric OR “older adults” OR “late life depression” OR “cardiovascular disease” OR “hospitalized” OR “hospitalized”). The recommended use, dosing ranges, cardiovascular effects, and general advantages and disadvantages of each of the drugs are discussed. Levomilnacipran and vilazodone have not received enough study to judge their safety in older patients or in those with, or at high risk for, cardiovascular disease. There is at least some evidence for possible adverse events with each of the other newer antidepressants that could be of concern in these patients. Nevertheless, with careful administration and attention to the potential adverse reactions for each drug, these may provide safe effective alternatives for older adults and patients with cardiovascular disease who do not respond to selective serotonin reuptake inhibitor antidepressants. However, more research on the safety and efficacy of these drugs in these specific patient populations is urgently needed.