Since their development, dental implants have become one of the most common procedures to rehabilitate patients with single missing teeth or fully edentulous jaws. As implants become more mainstream, determining the factors that affect osseointegration is extremely important. Medical risk factors identified to negatively affect osseointegration include diabetes and osteoporosis. However, other systemic conditions and medications that interfere with wound healing have not been as widely investigated. The aim of this systematic review was to evaluate the effect of systemic disorders including diabetes and osteoporosis on implant osseointegration. The aim was also to evaluate the effect of other diseases, such as neurocognitive diseases, cardiovascular disease, human immunodeficiency virus (HIV), hypothyroidism, rheumatoid arthritis, and medications, such as selective serotonin reuptake inhibitors (SSRIs), proton pump inhibitors (PPIs), and antihypertensives. Although the literature does not demonstrate that diabetes negatively affects implant osseointegration, most studies focus on well-controlled diabetics and the use of prophylactic antibiotics. In addition, studies have shown increased long-term bone and soft tissue complications. For osteoporosis, recent studies and reviews also fail to demonstrate a lower osseointegration rate. However, caution must be exercised in these patients due to the risk for osteonecrosis of the jaws (ONJ), especially in patients with bone malignancies. There is also no direct evidence that patients with HIV, cardiovascular disease, neurologic disorders, hypothyroidism, or rheumatoid arthritis have a decreased rate of implant osseointegration. However, some preliminary evidence suggests that medications such as SSRIs or PPIs may have a negative effect on implant osseointegration. These studies are fairly recent and must be validated with continuous research. Moreover, disease control, concomitant medications, and other comorbidities complicate implant osseointegration and must guide our treatment approaches and clinical guidelines.