Background: The impact of COVID-19 on adolescents with cerebral palsy (CP) and their families is underinvestigated, particularly in the Southeastern United States. Objective/Hypothesis: The objective of this study was to examine the impact of COVID-19 on lifestyle activities, general and mental health, and basic needs among a cohort of adolescents with CP in the Southeast U.S. The second purpose was to identify key factors that impacted their lifestyles. Methods: This was a cross-sectional survey of adolescents with CP (aged 10–19 years) who completed a child-modified version of the Coronavirus Disability Survey. Health and behavior items were associated with the perceived lifestyle impact of COVID-19. Results: A total of 101 respondents completed the survey (mean age: 14 ± 2 years). Respondents reported minimal to no change in general health since the COVID-19 outbreak. Basic needs were met for most families. Nearly all participants (94.1%) reported a mental health concern that resulted from COVID-19: 32.7% felt down or depressed; 47.5% felt little pleasure in doing things; and 64.4% felt isolated. Moreover, 74.3% reported decreased socialization, 51.5% reported reduced exercise participation, and 43.6% reported difficulties in obtaining medical care. Most participants (90.1%) were negatively affected by COVID-19, and key associated factors were reduced interactions with friends and family (p = 0.001), exercise participation (p = 0.016), interest in doing things (p = 0.005), worsened depression (p = 0.015), increased isolation from others (p = 0.02) and at home (p = 0.006), technological communication (p = 0.00), and virus exposure (p = 0.008). Conclusions: Study findings highlight problem areas that warrant urgent intervention among adolescents with CP located within the Southeast U.S.