The prevalence of autism spectrum disorder (ASD) continues to see a trend upward with a noticeable increase to 1 in 36 children less than 8 years of age in the recent MMWR. There are many factors linked to the substantially increased burden of seeking mental health services, and clinically these individuals are likely to present for impairments associated with co-occurring conditions. The advances in cutting-edge research and the understanding of co-occurring conditions in addition to psychosocial interventions have provided a window of opportunity for psychopharmacological interventions given the limited availability of therapeutics for core symptomatology. The off-label psychopharmacological treatments for these co-occurring conditions are central to clinical practice. However, the scattered evidence remains an impediment for practitioners to systematically utilize these options. The review collates the crucial scientific literature to provide stepwise treatment alternatives for individuals with ASD; with an aim to lead practitioners in making informed and shared decisions. There are many questions about the safety and tolerability of off-label medications; however, it is considered the best practice to utilize the available empirical data in providing psychoeducation for patients, families, and caregivers. The review also covers experimental medications and theoretical underpinnings to enhance further experimental studies. In summary, amidst the growing clinical needs for individuals with ASD and the lack of approved clinical treatments, the review addresses these gaps with a practical guide to appraise the risk and benefits of off-label medications.