There was a change in the pattern of substance usage among people who use substances during the COVID-19 pandemic period. This study aims to determine the effects of the COVID-19 pandemic on the pattern of substance usage among people who use drugs (PWUD) receiving treatment at the University Malaya Medical Centre (UMMC) as well as levels of anxiety and depression together with coping mechanisms and the factors affecting the pattern of substance use during COVID-19 pandemic period. A cross-sectional study was applied. The questionnaire used was the Mini-European Web Survey on Drugs (EWSD): COVID-19, Hospital Anxiety and Depression Scale (HADS), and Brief COPE Scale. In total, 130 PWUD were recruited. Of the participants, 36.2% of PWUD had not used/stopped the usage of illicit drugs/alcohol, 26.2% increased their usage, 20% decreased, and 14.6% used the same amount of illicit substances/alcohol during the COVID-19 pandemic period/restrictions. In addition, 28.5% of PWUD had an increased intention to seek professional support for drug counseling/treatment during the COVID-19 pandemic period. The prevalence anxiety and depression symptoms in PWUD according to HADS was 33% and 41.5%, respectively, with depression (p = 0.05) and isolation status (adjusted OR = 2.63, p < 0.05) being associated with an increase in alcohol/illicit substance use during the COVID-19 pandemic. PWUD who had increased their intention to seek professional support had significantly higher odds (adjusted OR = 4.42, p < 0.01) of reducing their alcohol/illicit substance use during the COVID-19 pandemic period. There were increased odds of maintaining alcohol/illicit substance usage among PWUD who practiced dysfunctional coping (adjusted OR = 3.87, p < 0.025) during the COVID-19 pandemic period. In conclusion, depression, isolation status, dysfunctional coping, and intention to seek professional support affected the pattern of alcohol/illicit substance use during the COVID-19 pandemic period. Strategies, substance rehabilitation/counseling, and proper mental health screening and the associated risk factors must be emphasized to prevent a further epidemic of substance use during the pandemic.